Submissions for variant NM_000059.4(BRCA2):c.7021C>T (p.Arg2341Cys)

gnomAD frequency: 0.00002  dbSNP: rs41293505

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130453	SCV000185317	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-24	criteria provided, single submitter	clinical testing	The p.R2341C variant (also known as c.7021C>T), located in coding exon 13 of the BRCA2 gene, results from a C to T substitution at nucleotide position 7021. The arginine at codon 2341 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been detected in a suspected HBOC family and in multiple patients diagnosed with breast cancer (Warren CR et al. Exp. Cell Res. 2011 Sep; 317:2099-109; Wong-Brown MW et al. Breast Cancer Res. Treat. 2015 Feb; 150(1):71-80; Penkert J et al. Breast Cancer Res, 2018 08;20:87). This alteration has also been detected in a cohort of 727 patients with personal and family history of pancreatic cancer (Zhen DB et al. Genet. Med., 2015 Jul;17:569-77). Additionally, this alteration was observed in with an allele frequency of 0.00014 in 7,051 unselected female breast cancer patients and was observed with an allele frequency of 0 in 11,241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083) and in 1/1358 non-cancer control individuals and in 0/57 cases, in a study looking at cancer predisposition mutations in patients with cutaneous melanoma and a history of at least two additional non-cutaneous melanoma primary cancers (Pritchard AL et al. PLoS One, 2018 Apr;13:e0194098). This amino acid position is not well 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.
GeneDx	RCV000160126	SCV000210413	uncertain significance	not provided	2023-07-19	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer or pancreatic cancer, but also in unaffected controls (Warren et al., 2011; Wong-Brown et al., 2015; Zhen et al., 2015; Momozawa et al., 2018; Penkert et al., 2018; Pritchard et al., 2018); Also known as 7249C>T; This variant is associated with the following publications: (PMID: 20858050, 21741379, 25682074, 25356972, 31131967, 30287823, 30086788, 29641532, 32123317, 29884841, 32377563)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000227614	SCV000283307	likely benign	Hereditary breast ovarian cancer syndrome	2025-01-05	criteria provided, single submitter	clinical testing
Counsyl	RCV000076986	SCV000785845	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2017-12-27	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130453	SCV000906543	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-09	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 2341 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 observed in individuals affected with breast cancer (PMID: 21741379, 25682074, 30086788, 30287823), pancreatic cancer (PMID: 25356972), and prostate cancer (PMID: 31214711). This variant has been identified in 6/250562 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	RCV000781128	SCV000918977	uncertain significance	not specified	2021-09-03	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.7021C>T (p.Arg2341Cys) results in a non-conservative amino acid change located in the Linker region (Warren_2011) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.2e-05 in 273044 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7021C>T has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Warren_ 2011, Wong-Brown_2015, Momozawa_2018) and was also found in one patient with pancreatic cancer (Zhen_2014). These reports however do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with pathogenic variants have been reported in UMD database (BRCA1 c.3048_3067del; p.Asn1018HisfsX3 and BRCA2 c.3744_3747delTGAG ; p.Ser1248ArgfsX10), providing supporting evidence for a benign role. The variant was found to have no effect on splicing (Wai_2020). Five other ClinVar submitters (evaluation after 2014) with four citing the variant as uncertain significance and one citing at likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Sema4, Sema4	RCV000130453	SCV002536295	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-03	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV004804050	SCV004844349	uncertain significance	BRCA2-related cancer predisposition	2024-07-20	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 2341 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. This variant did not impact function in a high throughput multiplexed NGS-based functional assay in mouse embryonic stem cells (PMID: 37922907). This variant has been observed in individuals affected with breast cancer (PMID: 21741379, 25682074, 30086788, 30287823), pancreatic cancer (PMID: 25356972), and prostate cancer (PMID: 31214711). This variant has been identified in 6/250562 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.
Baylor Genetics	RCV004566938	SCV005059045	uncertain significance	Familial cancer of breast	2024-02-18	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000076986	SCV000108783	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2008-07-01	no assertion criteria provided	clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735598	SCV000863736	likely benign	Breast and/or ovarian cancer	2012-05-10	no assertion criteria provided	clinical testing