ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4178C>T (p.Ala1393Val) (rs398122776)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000074528 SCV000108613 likely benign not specified 2015-07-24 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics RCV000165267 SCV000215983 likely benign Hereditary cancer-predisposing syndrome 2019-04-16 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other strong data supporting benign classification
Counsyl RCV000410711 SCV000488362 uncertain significance Breast-ovarian cancer, familial 2 2016-03-08 criteria provided, single submitter clinical testing
Invitae RCV000472348 SCV000549793 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-08-06 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 1393 of the BRCA2 protein (p.Ala1393Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs398122776, ExAC 0.01%). This variant has not been reported in the literature in individuals with a BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 89047). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0. The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000074528 SCV000694748 uncertain significance not specified 2019-09-09 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.4178C>T (p.Ala1393Val) 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 allele was found at a frequency of 4.1e-06 in 241110 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4178C>T has been reported in the literature without strong evidence for causality (Chen_2015, Wu_2014). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five other 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, three as likely benign and two as VUS. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Health, Inc RCV000165267 SCV000903138 benign Hereditary cancer-predisposing syndrome 2017-02-14 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001358513 SCV001554268 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Ala1393Val variant was identified in 1 of 684 proband chromosomes (frequency: 0.001) from individuals with gastric cancer and was present in 2 of 24,980 control chromosomes (frequency: 0.0008) from healthy individuals (Chen 2015, Momozawa 2018). The variant was identified in dbSNP (rs398122776) as “with uncertain significance allele”, in ClinVar (interpreted as "uncertain significance" by Invitae and 2 others, "likely benign" by Ambry Genetics and 1 other and "benign" by Color), LOVD 3.0 (observed 3x) and UMD-LSDB (observed 5x). The variant was identified in control databases in 1 of 236,638 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 15,100 chromosomes (freq: 0.00007), but not in the Other, Latino, European, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Ala1393 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. This variant is classified as a variant of uncertain significance.

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