Submissions for variant NM_000059.4(BRCA2):c.9905G>A (p.Arg3302Lys)

gnomAD frequency: 0.00001  dbSNP: rs80359249

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000509696	SCV000607783	uncertain significance	Hereditary cancer-predisposing syndrome	2024-08-30	criteria provided, single submitter	clinical testing	The p.R3302K variant (also known as c.9905G>A), located in coding exon 26 of the BRCA2 gene, results from a G to A substitution at nucleotide position 9905. The arginine at codon 3302 is replaced by lysine, an amino acid with highly similar properties. This amino acid position is highly 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.
Color Diagnostics, LLC DBA Color Health	RCV000509696	SCV000689233	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-30	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with lysine at codon 3302 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 at least four individuals affected with breast cancer and one unaffected individual (PMID: 12491499, 33471991; Leiden Open Variation Database DB-ID BRCA2_002114) and in an individual affected with adenocarcinoma (PMID: 28843361). A multifactorial analysis has reported tumor pathology, co-occurrence and family history likelihood ratios for pathogenicity of 1.77, 1.1022 and 0.1339, respectively (PMID: 31131967). This variant has been identified in 2/251204 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	RCV000588627	SCV000695278	uncertain significance	not provided	2017-04-21	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.9905G>A (p.Arg3302Lys) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution and 4/5 in silico tools predict a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing but ESE finder predicts that this variant may introduce an SF2/ASF ESE site at the locus. However, functional studies have shown that the variant has not effect on splicing via RNA analysis from a patient blood sample (Houdayer_2012). This variant was found in the large control database ExAC at a frequency of 0.0000082 (1/121326 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant with differing interpretations, "uncertain significance" and "likely benign." Taken together, this variant is classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available (ie, clinical and functional studies).
Counsyl	RCV000083164	SCV000785011	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2017-03-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588627	SCV000889196	uncertain significance	not provided	2020-10-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001309231	SCV001498725	likely benign	Hereditary breast ovarian cancer syndrome	2024-11-27	criteria provided, single submitter	clinical testing
GeneDx	RCV000588627	SCV001783016	uncertain significance	not provided	2019-10-08	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in at least one individual with breast cancer (Adem 2003); Also known as BRCA2 10133G>A; This variant is associated with the following publications: (PMID: 12491499, 22505045)
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003321492	SCV004027495	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004537217	SCV004116329	uncertain significance	BRCA2-related disorder	2023-04-05	criteria provided, single submitter	clinical testing	The BRCA2 c.9905G>A variant is predicted to result in the amino acid substitution p.Arg3302Lys. This variant has been reported in an individual with breast cancer (Table 1, Adem et al. 2003. PubMed ID: 12491499). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-32972555-G-A) and is interpreted as uncertain significance by the vast majority of submitters in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/52913/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health	RCV000083164	SCV004846244	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-02-24	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with lysine at codon 3302 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 at least four individuals affected with breast cancer and one unaffected individual (PMID: 12491499, 33471991; Leiden Open Variation Database DB-ID BRCA2_002114) and in an individual affected with adenocarcinoma (PMID: 28843361). A multifactorial analysis has reported tumor pathology, co-occurrence and family history likelihood ratios for pathogenicity of 1.77, 1.1022 and 0.1339, respectively (PMID: 31131967). This variant has been identified in 2/251204 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)	RCV000083164	SCV000115238	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-06-14	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000083164	SCV000145727	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing