ClinVar Genomic variation as it relates to human health

Variant summary: BRCA2 c.1627C>A (p.His543Asn) results in a conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 250880 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1627C>A has been reported in the literature in individuals affected with Hereditary Breast And/or Ovarian Cancer, however, authors classified the variant as VUS (examples: ElSaghir_2015, Henouda_2016, Alhuqail_B2018, Farra_2019, Salmi_2021 and Bisgin_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

This sequence change replaces histidine, which is basic and polar, with asparagine, which is neutral and polar, at codon 543 of the BRCA2 protein (p.His543Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with personal and/or family history of breast and/or ovarian cancer (PMID: 25777348, 26997744, 29297111, 30675319, 34242281). ClinVar contains an entry for this variant (Variation ID: 51158). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

This missense variant replaces histidine with asparagine at codon 543 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with breast cancer (PMID: 25777348, 26997744). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

The p.H543N variant (also known as c.1627C>A), located in coding exon 9 of the BRCA2 gene, results from a C to A substitution at nucleotide position 1627. The histidine at codon 543 is replaced by asparagine, an amino acid with similar properties. This alteration has been reported in multiple individuals of Algerian, Lebanese, Moroccan, and Turkish heritage with a personal and/or family history of HBOC-related cancer (El Saghir NS et al. Oncologist 2015 Apr;20(4):357-64; Henouda S et al. Dis. Markers 2016 Mar;2016:7869095; Farra C et al. Hered Cancer Clin Pract, 2019 Jan;17:4; Salmi F et al. PLoS One, 2021 Jul;16:e0254101; Bisgin A et al. Breast, 2022 Oct;65:15-22). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).

Observed in individuals with breast, ovarian, or prostate cancer (El Saghir et al., 2015; Henouda et al., 2016; Alhuqail et al., 2018; Salmi et al., 2021); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 1855C>A; This variant is associated with the following publications: (PMID: 30675319, 30263132, 26997744, 28814288, 25777348, 29297111, 32377563, 29884841, 35753294, 34242281)

The p.H543N variant (also known as c.1627C>A), located in coding exon 9 of the BRCA2 gene, results from a C to A substitution at nucleotide position 1627. The histidine at codon 543 is replaced by asparagine, an amino acid with similar properties. This alteration has been reported in an Algerian female with breast cancer and a Lebanese proband with familial breast cancer (El Saghir NS et al. Oncologist 2015 Apr;20(4):357-64; Henouda S et al. Dis. Markers 2016 Mar;2016:7869095). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be benign by computational verdict based on 10 benign predictions from BayesDel_addAF, DANN, EIGEN, FATHMM-MKL, M-CAP, MVP, MutationTaster, PrimateAI, REVEL and SIFT vs no pathogenic predictions. There is a ClinVar entry for this variant (ClinVar ID 51158) with 6 submissions: 5 as uncertain significance, and 1 as benign. Therefore, this variant is classified as of uncertain significance.

This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].

This missense variant replaces histidine with asparagine at codon 543 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with breast cancer (PMID: 25777348, 26997744), an individual affected with prostate cancer (PMID: 34242281), and two individuals with a personal or family history of breast and/or ovarian cancer (PMID: 30675319, 35753294). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

The BRCA2 p.His543Asn variant was identified in 2 of 580 proband chromosomes (frequency: 0.003) from individuals or families with breast cancer (El Saghir 2015, Henouda 2016). The variant was identified in dbSNP (rs80358446) as “with uncertain significance allele”, ClinVar (classified as uncertain significance by Ambry Genetics, Color, BIC and 1 other submitter; and as likely benign by our laboratory), LOVD 3.0 (observed 2x) and UMD-LSDB (observed 2x). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The variant was identified in our laboratory in an individual with a pathogenic BRCA2 variant (c.9097dup, p.Thr3033Asnfs*11). The p.His543 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.