ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.1255T>C (p.Cys419Arg)

dbSNP: rs876658829
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000214848 SCV000274586 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-30 criteria provided, single submitter clinical testing The p.C419R variant (also known as c.1255T>C), located in coding exon 9 of the BRCA2 gene, results from a T to C substitution at nucleotide position 1255. The cysteine at codon 419 is replaced by arginine, an amino acid with highly dissimilar properties. This alteration was identified in 1/715 Korean patients with breast cancer (Park KS et al. Genet. Med., 2016 12;18:1250-1257). 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.
Color Diagnostics, LLC DBA Color Health RCV000214848 SCV000914012 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-30 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001230481 SCV001402962 likely benign Hereditary breast ovarian cancer syndrome 2022-09-01 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine, University of Washington RCV000214848 SCV003849944 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).
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000500546 SCV000591732 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 2 no assertion criteria provided clinical testing The BRCA2 p.Cys419Arg variant was not identified in the literature, nor was it identified in the dbSNP, NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC), HGMD, LOVD, COSMIC, ClinVar, GeneInsight VariantWire, BIC or UMD databases. The variant occurs outside of the splicing consensus sequence and five in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The p.Cys419 residue is not conserved in mammals and four out of five 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. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance.

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