VCV000127482.67 - ClinVar

NM_000057.4(BLM):c.2119C>T (p.Pro707Ser)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(20)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Uncertain significance(2); Benign(2); Likely benign(10)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000057.4(BLM):c.2119C>T (p.Pro707Ser)

Variation ID: 127482 Accession: VCV000127482.67

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 15q26.1 15: 90765340 (GRCh38) [ NCBI UCSC ] 15: 91308570 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jun 4, 2015	Oct 20, 2024	Jun 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000057.4:c.2119C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000048.1:p.Pro707Ser	missense
NM_001287246.2:c.2119C>T	NP_001274175.1:p.Pro707Ser	missense
NM_001287247.2:c.2119C>T	NP_001274176.1:p.Pro707Ser	missense
NM_001287248.2:c.994C>T	NP_001274177.1:p.Pro332Ser	missense
NC_000015.10:g.90765340C>T
NC_000015.9:g.91308570C>T
NG_007272.1:g.52969C>T
LRG_20:g.52969C>T
LRG_20t1:c.2119C>T

... more HGVS ... less HGVS

Protein change

P707S, P332S

Other names

p.P707S:CCT>TCT

Canonical SPDI

NC_000015.10:90765339:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00100 (T)

Allele frequency Help The frequency of the allele represented by this VCV record.

Exome Aggregation Consortium (ExAC) 0.00161

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00162

The Genome Aggregation Database (gnomAD), exomes 0.00164

The Genome Aggregation Database (gnomAD) 0.00172

1000 Genomes Project 30x 0.00094

1000 Genomes Project 0.00100

Trans-Omics for Precision Medicine (TOPMed) 0.00154

Links

ClinGen: CA274808 dbSNP: rs146077918 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
BLM		-	-	GRCh38 GRCh37	4378	4430

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not specified	Likely benign (3)	criteria provided, multiple submitters, no conflicts	Apr 30, 2024	RCV000115288.14
Bloom syndrome	Conflicting interpretations of pathogenicity (6)	criteria provided, conflicting classifications	Jan 31, 2024	RCV000172805.25
Hereditary cancer-predisposing syndrome	Likely benign (2)	criteria provided, multiple submitters, no conflicts	May 28, 2021	RCV000563887.5
not provided	Conflicting interpretations of pathogenicity (8)	criteria provided, conflicting classifications	Jun 1, 2024	RCV000857591.37
BLM-related disorder	Likely benign (1)	no assertion criteria provided	Apr 29, 2019	RCV003952548.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely benign (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Bloom syndrome Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001139703.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020
Likely benign (May 04, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000149197.12 First in ClinVar: May 17, 2014 Last updated: Jul 24, 2021	Comment: This variant is associated with the following publications: (PMID: 23129629, 21815139, 17407155)
Likely benign (Dec 08, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: no Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV002069592.1 First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022
Uncertain significance (Nov 03, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden Accession: SCV002010562.3 First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023
Benign (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Bloom syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000555834.9 First in ClinVar: Jun 04, 2015 Last updated: Feb 20, 2024
Likely benign (Jul 12, 2018)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000672872.5 First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024	Publications: PubMed (2) PubMed: 21815139‚ 23129629 Comment: This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more) This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Likely benign (Apr 30, 2024)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000918654.3 First in ClinVar: Jun 02, 2019 Last updated: Jul 15, 2024	Publications: PubMed (7) PubMed: 23028338‚ 17407155‚ 23129629‚ 21815139‚ 30541756‚ 33558524‚ 33318203 Comment: Variant summary: BLM c.2119C>T (p.Pro707Ser) results in a non-conservative amino acid change located in the Helicase superfamily 1/2, ATP-binding domain of the encoded protein sequence. … (more) Variant summary: BLM c.2119C>T (p.Pro707Ser) results in a non-conservative amino acid change located in the Helicase superfamily 1/2, ATP-binding domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0016 in 251444 control chromosomes, predominantly at a frequency of 0.0024 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in BLM causing Bloom Syndrome (0.0016 vs 0.0035), allowing no conclusion about variant significance. c.2119C>T has been reported in the literature in individuals affected with breast cancer and mesothelioma and in cohorts from Bloom syndrome registries (German_2007, Sokolenko_2012, Thompson_2012, Bononi_2020, Moradian_2021). These reports do not provide unequivocal conclusions about association of the variant with Bloom Syndrome. Co-occurrences with other pathogenic variants have been reported in patients with breast cancer who did not manifest a full blown phenotype of Bloom syndrome (BLM c.1642C>T, p.Q548X - twice (Sokolenko_2012), phase not provided). This provides additional supporting evidence for a benign role. A functional study, Mirzaei_2012, evaluated the variants affect on hypersensitivity to the DNA-damaging agent hydroxyurea and found the variant to act comparable to wild-type function. The following publications have been ascertained in the context of this evaluation (PMID: 33318203, 17407155, 23129629, 33558524, 30541756, 21815139, 23028338). ClinVar contains an entry for this variant (Variation ID: 127482). Based on the evidence outlined above, the variant was classified as likely benign. (less)
Likely benign (Oct 30, 2014)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Bloom syndrome Affected status: unknown Allele origin: germline	Pathway Genomics Accession: SCV000223745.1 First in ClinVar: Jun 04, 2015 Last updated: Jun 04, 2015	Publications: PubMed (2) PubMed: 21815139‚ 17407155
Likely benign (Nov 25, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000337707.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=BLM Number of individuals with the variant: 1 Zygosity: Single Heterozygote Sex: mixed
Uncertain significance (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Bloom syndrome Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001278688.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (3) PubMed: 21815139‚ 23129629‚ 17407155 Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
Likely benign (May 28, 2021)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002529237.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Benign (Jul 07, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Bloom syndrome Affected status: yes Allele origin: germline	KCCC/NGS Laboratory, Kuwait Cancer Control Center Accession: SCV004016382.1 First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023
Likely benign (Jan 30, 2023)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV004222444.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Publications: PubMed (4) PubMed: 23129629‚ 21815139‚ 17407155‚ 33318203
Likely benign (Jun 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001149589.27 First in ClinVar: Feb 03, 2020 Last updated: Oct 20, 2024	Comment: BLM: BP4 Number of individuals with the variant: 14
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001929792.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001951187.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Likely benign (Jun 13, 2017)	no assertion criteria provided Method: clinical testing	Bloom syndrome Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002088033.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022
Likely benign (Apr 29, 2019)	no assertion criteria provided Method: clinical testing	BLM-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004771952.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001742331.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001971847.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
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Comment:

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Comment:

Variant summary: BLM c.2119C>T (p.Pro707Ser) results in a non-conservative amino acid change located in the Helicase superfamily 1/2, ATP-binding domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0016 in 251444 control chromosomes, predominantly at a frequency of 0.0024 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in BLM causing Bloom Syndrome (0.0016 vs 0.0035), allowing no conclusion about variant significance. c.2119C>T has been reported in the literature in individuals affected with breast cancer and mesothelioma and in cohorts from Bloom syndrome registries (German_2007, Sokolenko_2012, Thompson_2012, Bononi_2020, Moradian_2021). These reports do not provide unequivocal conclusions about association of the variant with Bloom Syndrome. Co-occurrences with other pathogenic variants have been reported in patients with breast cancer who did not manifest a full blown phenotype of Bloom syndrome (BLM c.1642C>T, p.Q548X - twice (Sokolenko_2012), phase not provided). This provides additional supporting evidence for a benign role. A functional study, Mirzaei_2012, evaluated the variants affect on hypersensitivity to the DNA-damaging agent hydroxyurea and found the variant to act comparable to wild-type function. The following publications have been ascertained in the context of this evaluation (PMID: 33318203, 17407155, 23129629, 33558524, 30541756, 21815139, 23028338). ClinVar contains an entry for this variant (Variation ID: 127482). Based on the evidence outlined above, the variant was classified as likely benign.

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Germline mutational spectrum in Armenian breast cancer patients suspected of hereditary breast and ovarian cancer.	Moradian MM	Human genome variation	2021	PMID: 33558524
Heterozygous germline BLM mutations increase susceptibility to asbestos and mesothelioma.	Bononi A	Proceedings of the National Academy of Sciences of the United States of America	2020	PMID: 33318203
BRCA1/2 Functional Loss Defines a Targetable Subset in Leiomyosarcoma.	Seligson ND	The oncologist	2019	PMID: 30541756
Non-Bloom syndrome-associated partial and total loss-of-function variants of BLM helicase.	Mirzaei H	Proceedings of the National Academy of Sciences of the United States of America	2012	PMID: 23129629
Exome sequencing identifies rare deleterious mutations in DNA repair genes FANCC and BLM as potential breast cancer susceptibility alleles.	Thompson ER	PLoS genetics	2012	PMID: 23028338
High prevalence and breast cancer predisposing role of the BLM c.1642 C>T (Q548X) mutation in Russia.	Sokolenko AP	International journal of cancer	2012	PMID: 21815139
Syndrome-causing mutations of the BLM gene in persons in the Bloom's Syndrome Registry.	German J	Human mutation	2007	PMID: 17407155
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=BLM	-	-	-	-

Text-mined citations for rs146077918 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_000057.4(BLM):c.2119C>T (p.Pro707Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs146077918 ...