VCV000092393.38 - ClinVar

NM_000057.4(BLM):c.2603C>T (p.Pro868Leu)

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.

(19)

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.

Benign

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000057.4(BLM):c.2603C>T (p.Pro868Leu)

Variation ID: 92393 Accession: VCV000092393.38

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 15q26.1 15: 90782869 (GRCh38) [ NCBI UCSC ] 15: 91326099 (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 9, 2014	Sep 29, 2024	Feb 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000057.4:c.2603C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000048.1:p.Pro868Leu	missense
NM_001287246.2:c.2603C>T	NP_001274175.1:p.Pro868Leu	missense
NM_001287247.2:c.2603C>T	NP_001274176.1:p.Pro868Leu	missense
NM_001287248.2:c.1478C>T	NP_001274177.1:p.Pro493Leu	missense
NC_000015.10:g.90782869C>T
NC_000015.9:g.91326099C>T
NG_007272.1:g.70498C>T
LRG_20:g.70498C>T
LRG_20t1:c.2603C>T	LRG_20p1:p.Pro868Leu
	P54132:p.Pro868Leu

... more HGVS ... less HGVS

Protein change

P868L, P493L

Other names

Canonical SPDI

NC_000015.10:90782868: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.

0.05132 (T)

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

1000 Genomes Project 30x 0.05044

1000 Genomes Project 0.05132

Trans-Omics for Precision Medicine (TOPMed) 0.06105

The Genome Aggregation Database (gnomAD) 0.06742

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.06804

Links

ClinGen: CA090891 UniProtKB: P54132#VAR_022298 dbSNP: rs2227935 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.
Bloom syndrome	Benign (8)	criteria provided, multiple submitters, no conflicts	Feb 1, 2024	RCV000144575.33
not specified	Benign (5)	criteria provided, multiple submitters, no conflicts	Mar 1, 2013	RCV000078058.31
Hereditary cancer-predisposing syndrome	Benign (1)	criteria provided, single submitter	Aug 12, 2016	RCV000568944.11
not provided	Benign (4)	criteria provided, multiple submitters, no conflicts	Aug 31, 2016	RCV000586013.14
Hereditary disease	Benign (1)	no assertion criteria provided	Sep 16, 2020	RCV001824121.9

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.
Benign (Mar 01, 2013)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000109896.8 First in ClinVar: Jan 23, 2014 Last updated: May 03, 2018	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
Benign (Mar 06, 2018)	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: SCV000394420.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
Benign (Mar 03, 2015)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001865926.1 First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021	Comment: This variant is associated with the following publications: (PMID: 29484706, 24728327, 24816114, 26788541, 27153395, 19945966, 23129629)
Benign (Aug 12, 2016)	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: SCV000672859.5 First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024	Comment: This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more) This alteration is classified as 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)
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NOT SPECIFIED Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000301738.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016
Benign (Aug 31, 2016)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000694478.1 First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018	Publications: PubMed (2) PubMed: 26788541‚ 23129629 Comment: Variant summary: The BLM c.2603C>T (p.Pro868Leu) variant involves the alteration of a conserved nucleotide. 2/2 in silico tools predict a damaging outcome for this variant. … (more) Variant summary: The BLM c.2603C>T (p.Pro868Leu) variant involves the alteration of a conserved nucleotide. 2/2 in silico tools predict a damaging outcome for this variant. This variant was found in 6732/120402 control chromosomes (223 homozygotes) at a frequency of 0.0559127, which is approximately 16 times the estimated maximal expected allele frequency of a pathogenic BLM variant (0.0035355), suggesting this variant is likely a benign polymorphism. Functional studies suggest partial loss of funciton (Mirzaei_2012, Shastri_2015), however the prevalence in the general population as well as numerous homozygous occurrences indicate this variant is insufficient for full-scale Bloom syndrome. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. Taken together, this variant is classified as benign. (less)
Benign (May 18, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Bloom syndrome Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV001623022.1 First in ClinVar: May 23, 2021 Last updated: May 23, 2021	Sex: mixed
Benign (Feb 04, 2021)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021) Method: clinical testing	Bloom syndrome Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV002049304.1 First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 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: SCV004016380.1 First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023
Benign (Feb 01, 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: SCV001000589.6 First in ClinVar: Dec 17, 2019 Last updated: Feb 28, 2024
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005295470.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Likely benign (Jul 24, 2014)	no assertion criteria provided Method: clinical testing	Bloom syndrome Affected status: unknown Allele origin: germline	Pathway Genomics Accession: SCV000189874.1 First in ClinVar: Oct 19, 2014 Last updated: Oct 19, 2014
Likely benign (-)	no assertion criteria provided Method: clinical testing	AllHighlyPenetrant (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000150444.2 First in ClinVar: May 17, 2014 Last updated: Sep 01, 2014	Comment: Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated … (more) Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. (less)
Benign (-)	no assertion criteria provided Method: clinical testing	Bloom syndrome Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV000733481.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018
Benign (May 20, 2019)	no assertion criteria provided Method: clinical testing	Bloom syndrome Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001190658.1 First in ClinVar: Mar 29, 2020 Last updated: Mar 29, 2020
Benign (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Hereditary Disorder Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001454859.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
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: SCV001932382.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified 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: SCV001957523.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
not provided (Sep 19, 2013)	no classification provided Method: reference population	AllHighlyPenetrant Affected status: unknown Allele origin: germline	ITMI Accession: SCV000084373.1 First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014 Comment: Please see associated publication for description of ethnicities	Publications: PubMed (1) PubMed: 24728327 Observation 1: Ethnicity/Population group: Whole_cohort Observation 2: Ethnicity/Population group: African Observation 3: Ethnicity/Population group: African_European Observation 4: Ethnicity/Population group: Central_Asian Observation 5: Ethnicity/Population group: East_Asian Observation 6: Ethnicity/Population group: European Observation 7: Ethnicity/Population group: Hispanic
click to load more click to collapse

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Comment:

This alteration is classified as 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: The BLM c.2603C>T (p.Pro868Leu) variant involves the alteration of a conserved nucleotide. 2/2 in silico tools predict a damaging outcome for this variant. This variant was found in 6732/120402 control chromosomes (223 homozygotes) at a frequency of 0.0559127, which is approximately 16 times the estimated maximal expected allele frequency of a pathogenic BLM variant (0.0035355), suggesting this variant is likely a benign polymorphism. Functional studies suggest partial loss of funciton (Mirzaei_2012, Shastri_2015), however the prevalence in the general population as well as numerous homozygous occurrences indicate this variant is insufficient for full-scale Bloom syndrome. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. Taken together, this variant is classified as benign.

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
Cellular defects caused by hypomorphic variants of the Bloom syndrome helicase gene BLM.	Shastri VM	Molecular genetics & genomic medicine	2015	PMID: 26788541
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
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=BLM	-	-	-	-

Text-mined citations for rs2227935 ...

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 Dec 07, 2024

ClinVar Genomic variation as it relates to human health

NM_000057.4(BLM):c.2603C>T (p.Pro868Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs2227935 ...