Submissions for variant NM_000059.4(BRCA2):c.6323G>T (p.Arg2108Leu)

dbSNP: rs35029074

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000168279	SCV000218951	likely benign	Hereditary breast ovarian cancer syndrome	2024-12-12	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000213911	SCV000273890	likely benign	Hereditary cancer-predisposing syndrome	2015-11-05	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	RCV001703980	SCV000530979	likely benign	not provided	2021-05-05	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29884136)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000423308	SCV000919000	uncertain significance	not specified	2020-12-18	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.6323G>T (p.Arg2108Leu) 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 was absent in 245876 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6323G>T has been reported in the literature in individuals affected with breast cancer before 30, prostate cancer (Pajares_2018) and in a study of individuals with a personal and/or family history of BRCA-related cancers (Pirim_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least one co-occurrence with another pathogenic variant has been reported in the UMD database (BRCA1 c.4065_4068delTCAA, p.Asn1355LysfsX10), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Color Diagnostics, LLC DBA Color Health	RCV000213911	SCV001353899	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-06	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with leucine at codon 2108 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 one individual affected with breast cancer and three individuals affected with prostate cancer, however, one of the individuals also has a pathogenic allele in BRCA1 (PMID: 29884136). This variant also has been detected in a breast cancer case-control meta-analysis in 0/60463 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001051). A multifactorial analysis reported co-occurrence and family history likelihood ratios for pathogenicity of 1.0246 and 1.7649, respectively (PMID: 31131967). 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001703980	SCV001471813	uncertain significance	not provided	2020-02-27	criteria provided, single submitter	clinical testing	The BRCA2 c.6323G>T; p.Arg2108Leu variant (rs35029074) is reported in the literature in individuals affected with breast or prostate cancer, but has also been identified in an individual with a pathogenic variant in BRCA1 (Pajares 2018). This variant is reported in ClinVar (Variation ID: 91444), but is absent from general population databases (Exome Variant Server, Genome Aggregation Database). The arginine at codon 2108 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of the p.Arg2108Leu variant is uncertain at this time. References: Pajares B et al. Hereditary breast and ovarian cancer in Andalusian families: a genetic population study. BMC Cancer. 2018 Jun 8;18(1):647.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000213911	SCV003852430	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).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001703980	SCV004220500	uncertain significance	not provided	2023-06-22	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals and families with a BRCA2 related disorder (PMID: 29884136 (2016), 32599251 (2020)). This variant is also located in a region of the BRCA2 gene that is tolerant to missense sequence changes (PMID: 31911673 (2020)). In a large-scale breast cancer association study, the variant was observed in individuals with breast cancer as well as in unaffected individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA2)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Sharing Clinical Reports Project (SCRP)	RCV000076961	SCV000108758	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-03-08	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000076961	SCV000146826	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2003-12-23	no assertion criteria provided	clinical testing