ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.4361T>C (p.Val1454Ala) (rs587782606)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131975 SCV000187033 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000199725 SCV000254986 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-31 criteria provided, single submitter clinical testing This sequence change replaces valine with alanine at codon 1454 of the BRCA1 protein (p.Val1454Ala). The valine residue is weakly conserved and there is a small physicochemical difference between valine and alanine. This variant is present in population databases (rs587782606, ExAC 0.001%). This variant has been observed in individual(s) with a personal and/or family history of ovarian cancer (PMID: 26306726). ClinVar contains an entry for this variant (Variation ID: 142639). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but 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.
Counsyl RCV000411768 SCV000489053 uncertain significance Breast-ovarian cancer, familial 1 2016-08-09 criteria provided, single submitter clinical testing
GeneDx RCV000486159 SCV000567779 uncertain significance not provided 2015-08-20 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.4361T>C at the cDNA level, p.Val1454Ala (V1454A) at the protein level, and results in the change of a Valine to an Alanine (GTA>GCA). Using alternate nomenclature, this variant would be defined as BRCA1 4480T>C. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Val1454Ala was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Valine and Alanine share similar properties, this is considered a conservative amino acid substitution. BRCA1 Val1454Ala occurs at a position that is not conserved and is located in the SCD domain (Narod 2004, Clark 2012). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BRCA1 Val1454Ala is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color RCV000131975 SCV000911788 likely benign Hereditary cancer-predisposing syndrome 2016-03-30 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781008 SCV000918756 uncertain significance not specified 2018-07-10 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.4361T>C (p.Val1454Ala) 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 8.1e-06 in 245656 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.4361T>C, has been reported in the literature in one individual affected with Hereditary Breast and Ovarian Cancer (Minucci_2015). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variant(s) have been reported (BRCA2 c.6468_6469delTC, p.Q2157fs*18), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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