Submissions for variant NM_000059.4(BRCA2):c.4672A>C (p.Ser1558Arg)

gnomAD frequency: 0.00001  dbSNP: rs587782822

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132397	SCV000187489	likely benign	Hereditary cancer-predisposing syndrome	2019-12-06	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV000255433	SCV000321462	uncertain significance	not provided	2023-10-20	criteria provided, single submitter	clinical testing	Observed in individuals undergoing multi-gene panel testing; however, no information on clinical history was provided (PMID: 31853058); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 4900A>C; This variant is associated with the following publications: (PMID: 29884841, 32377563, 31853058)
Counsyl	RCV000411787	SCV000489365	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-09-27	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000542360	SCV000635395	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-08-04	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 1558 of the BRCA2 protein (p.Ser1558Arg). This variant is present in population databases (rs587782822, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 142923). 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.
Color Diagnostics, LLC DBA Color Health	RCV000132397	SCV001349974	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-05	criteria provided, single submitter	clinical testing	This missense variant replaces serine with arginine at codon 1558 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 not been reported in individuals affected with BRCA2-related disorders in the literature. This variant has been identified in 2/251004 chromosomes 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.
Genetic Services Laboratory, University of Chicago	RCV001818333	SCV002070217	uncertain significance	not specified	2020-03-17	criteria provided, single submitter	clinical testing	DNA sequence analysis of the BRCA2 gene demonstrated a sequence change, c.4672A>C, in exon 11 that results in an amino acid change, p.Ser1558Arg. This sequence change has been described in the gnomAD database in two individuals (dbSNP rs587782822) and has been reported in a single individual with breast cancer (PMID: 21520333). The p.Ser1558Arg change affects a poorly conserved amino acid residue located in a domain of the BRCA2 protein that is known to be functional. The p.Ser1558Arg substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Ser1558Arg change remains unknown at this time.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000132397	SCV003852004	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001818333	SCV004223488	uncertain significance	not specified	2023-11-08	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.4672A>C (p.Ser1558Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251004 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.4672A>C in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Five submitters classified the variant as uncertain significance and two classified it as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV000411787	SCV004845716	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-11-20	criteria provided, single submitter	clinical testing	This missense variant replaces serine with arginine at codon 1558 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/251004 chromosomes 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.