Submissions for variant NM_000059.4(BRCA2):c.5344C>A (p.Gln1782Lys)

gnomAD frequency: 0.00001  dbSNP: rs80358757

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000044636	SCV000072649	likely benign	Hereditary breast ovarian cancer syndrome	2023-12-10	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000132498	SCV000187592	likely benign	Hereditary cancer-predisposing syndrome	2018-09-13	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Counsyl	RCV000113421	SCV000489074	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-08-19	criteria provided, single submitter	clinical testing
GeneDx	RCV001284428	SCV000520027	likely benign	not provided	2019-04-30	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 20730485, 15728167)
Color Diagnostics, LLC DBA Color Health	RCV000132498	SCV000906917	likely benign	Hereditary cancer-predisposing syndrome	2018-10-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000421612	SCV001361957	uncertain significance	not specified	2019-10-14	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5344C>A (p.Gln1782Lys) results in a conservative amino acid change located in the BRCA2 repeat region (IPR002093). Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.1e-06 in 281592 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5344C>A has been reported in the literature in an individual affected with breast cancer (Claus_2005). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrence with another pathogenic BRCA2 variant, c.4889C>G (p.Ser1630X), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions (evaluation after 2014) cite the variant twice as likely benign and twice as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284428	SCV001470221	uncertain significance	not provided	2020-02-20	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000132498	SCV003847175	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).
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113421	SCV000146598	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000113421	SCV001553959	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing	The BRCA2 p.Gln1782Lys variant was identified in literature in a patient with ductal carcinoma in situ, with a co-occurring, pathogenic BRCA2 variant: p.S1630X (Claus 2005). The variant was also identified in dbSNP (ID: rs80358757) as "With Pathogenic, Uncertain significance allele", ClinVar (classified as uncertain significance by Invitae, Counsyl and BIC; and as likely benign by Ambry Genetics and Gene Dx), and in UMD-LSDB (2x as unclassified variant). The variant was not identified in LOVD 3.0. The variant was identified in control databases in 2 of 276110 chromosomes at a frequency of 0.000007 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the African population in 2 of 23954 chromosomes (freq: 0.00008), while the variant was not observed in the Other, Latino, European, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Gln1782 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.