Submissions for variant NM_000059.4(BRCA2):c.5937C>G (p.Ser1979Arg)

gnomAD frequency: 0.00002  dbSNP: rs28897737

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000587913	SCV000210375	uncertain significance	not provided	2024-02-27	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 6165C>G; This variant is associated with the following publications: (PMID: 18724707, 21120943, 26992456, 25348012, 31131967, 31911673, 29884841, 32377563, 31853058, 29684080, 9002670, 22193408)
Ambry Genetics	RCV000167183	SCV000218019	uncertain significance	Hereditary cancer-predisposing syndrome	2024-06-20	criteria provided, single submitter	clinical testing	The p.S1979R variant (also known as c.5937C>G), located in coding exon 10 of the BRCA2 gene, results from a C to G substitution at nucleotide position 5937. The serine at codon 1979 is replaced by arginine, an amino acid with dissimilar properties. In one study, this variant was observed in 1/1525 unrelated patients who had BRCA1/2 genetic testing due to a personal and/or family history suspicious for Hereditary Breast and/or Ovarian Cancer syndrome (Caux-Moncoutier V et al. Hum Mutat, 2011 Mar;32:325-34). In a study of whole-exome sequencing in patients with features of Cowden syndrome (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS) and negative PTEN testing, this alteration was identified in 0/87 patients with CS or BRRS and 1/3476 patients from The Cancer Genome Atlas (Yehia L et al. PLoS Genet, 2018 04;14:e1007352). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000168414	SCV000219108	likely benign	Hereditary breast ovarian cancer syndrome	2025-01-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000031590	SCV000488008	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2015-12-11	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000167183	SCV000683742	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-08	criteria provided, single submitter	clinical testing	This missense variant replaces serine with arginine at codon 1979 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_002908) and an individual with personal or family history of breast or ovarian cancer (PMID 21120943). This variant has been identified in 6/250684 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001268976	SCV000694920	uncertain significance	not specified	2024-06-17	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5937C>G (p.Ser1979Arg) results in a non-conservative amino acid change located in the seventh BRCA2 repeat (IPR002093) of the encoded protein sequence. The BRCA2 repeat region consists of eight repeats (BRC) that are critical for binding to RAD51, where BRC1-4 and BRC7-8 are highly conserved and participate in Rad51 binding [PMID 10551859]. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 250684 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5937C>G has been reported in the literature in an individual with a personal and/or family history of breast and/or ovarian cancer (Caux-Moncoutier_2011), however, without strong evidence for causality (i.e. no cosegregation- and co-occurrence data were provided). This report does 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. The following publications have been ascertained in the context of this evaluation (PMID: 21120943, 25348012, 18724707, 26992456). ClinVar contains an entry for this variant (Variation ID: 38009). Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587913	SCV001133844	uncertain significance	not provided	2024-09-21	criteria provided, single submitter	clinical testing	The BRCA2 c.5937C>G (p.Ser1979Arg) variant has been reported in the published literature in individuals with a personal or family history of breast and/or ovarian cancer (PMIDs: 21120943 (2011), 32720237 (2021), 33471991 (2021) see also LOVD (https://databases.lovd.nl/shared/)). This variant has also been reported in one or more individuals affected with thyroid carcinoma (PMID: 29684080 (2018)). The frequency of this variant in the general population, 0.000044 (5/113458 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798049	SCV002043294	uncertain significance	Breast and/or ovarian cancer	2020-02-05	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000167183	SCV003850799	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).
All of Us Research Program, National Institutes of Health	RCV004803052	SCV004846673	uncertain significance	BRCA2-related cancer predisposition	2024-09-27	criteria provided, single submitter	clinical testing	This missense variant replaces serine with arginine at codon 1979 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_002908) and an individual with personal or family history of breast or ovarian cancer (PMID 21120943). This variant has been identified in 6/250684 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.
Sharing Clinical Reports Project (SCRP)	RCV000031590	SCV000054196	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2007-02-15	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031590	SCV000146733	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing