Submissions for variant NM_007294.4(BRCA1):c.4361T>C (p.Val1454Ala)

gnomAD frequency: 0.00001  dbSNP: rs587782606

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131975	SCV000187033	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-16	criteria provided, single submitter	clinical testing	The p.V1454A variant (also known as c.4361T>C), located in coding exon 12 of the BRCA1 gene, results from a T to C substitution at nucleotide position 4361. The valine at codon 1454 is replaced by alanine, an amino acid with similar properties. This alteration has been identified in individuals diagnosed with breast and/or ovarian cancer (Minucci A et al. Expert Rev. Mol. Diagn., 2015 Aug;15:1383-403; Germani A et al. Oncotarget, 2018 Sep;9:33648-33655; Santonocito C et al. Cancers (Basel), 2020 May;12:). 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.
Invitae	RCV000199725	SCV000254986	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-10-09	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 1454 of the BRCA1 protein (p.Val1454Ala). This variant is present in population databases (rs587782606, gnomAD 0.002%). This missense change has been observed in individual(s) with a personal and/or family history of breast and ovarian cancer (PMID: 26306726, 30263092, 32438681). ClinVar contains an entry for this variant (Variation ID: 142639). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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, susceptibility to, 1	2016-08-09	criteria provided, single submitter	clinical testing
GeneDx	RCV000486159	SCV000567779	uncertain significance	not provided	2022-03-31	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with breast and/or ovarian cancer (Minucci 2015, Germani 2018, Santonocito 2020); Also known as 4480T>C; This variant is associated with the following publications: (PMID: 15343273, 22737296, 26306726, 30263092, 32438681)
Color Diagnostics, LLC DBA Color Health	RCV000131975	SCV000911788	likely benign	Hereditary cancer-predisposing syndrome	2016-03-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781008	SCV000918756	uncertain significance	not specified	2023-10-06	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 8e-06 in 250884 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4361T>C has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g., Minucci_2015, Dorling_2021, Germani_2018, Santonocito_2020) however without strong evidence for causality (e.g., lack of co-segregation data). These reports therefore do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one co-occurrence with another pathogenic variant has been observed at our laboratory (BRCA2 c.6468_6469delTC, p.Q2157fs*18; internal testing), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33471991, 30263092, 26306726, 32438681). Six ClinVar submitters (evaluation after 2014) have cited the variant, with 5 submitters classifying the variant as uncertain significance and one submitter classifying the variant as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000781008	SCV002046148	uncertain significance	not specified	2021-05-20	criteria provided, single submitter	clinical testing