Submissions for variant NM_007294.4(BRCA1):c.3914A>T (p.Asp1305Val)

dbSNP: rs431825402

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000549261	SCV000635930	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-01-19	criteria provided, single submitter	clinical testing	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. ClinVar contains an entry for this variant (Variation ID: 96920). This missense change has been observed in individual(s) with breast cancer (PMID: 21520333, 31409081). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 1305 of the BRCA1 protein (p.Asp1305Val). 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.
Color Diagnostics, LLC DBA Color Health	RCV000775151	SCV000909285	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-11	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with valine at codon 1305 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has reported that this variant does not impact BRCA1 function in a homology-mediated DNA repair and sensitivity to cisplatin and PARP inhibitor assays (PMID: 32546644). This variant has been detected in a suspected hereditary breast and ovarian cancer family (PMID: 31409081) and it also has been detected in a breast cancer case-control meta-analysis in 1/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_002612). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000775151	SCV001183042	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-14	criteria provided, single submitter	clinical testing	The p.D1305V variant (also known as c.3914A>T), located in coding exon 9 of the BRCA1 gene, results from an A to T substitution at nucleotide position 3914. The aspartic acid at codon 1305 is replaced by valine, an amino acid with highly dissimilar properties. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002307392	SCV002600637	likely benign	not specified	2022-10-21	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.3914A>T (p.Asp1305Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251160 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3914A>T has been reported in the literature in individuals with suspected predisposition to Hereditary Breast And Ovarian Cancer Syndrome (Machackova_2019) . This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function (Bouwman_2020). These results showed no damaging effect of this variant on ability to complement BRCA1-deficient mouse embryonic stem cells in homologous recombination DNA repair (HRR) using cisplatin and olaparib sensitivity assays and a direct GFP HRR assay. HDR assays qualify as a recognized gold standard on the basis of updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) working group. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000775151	SCV003847832	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).
Sharing Clinical Reports Project (SCRP)	RCV000083041	SCV000115115	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2008-01-24	no assertion criteria provided	clinical testing