Submissions for variant NM_007294.4(BRCA1):c.734A>T (p.Asp245Val)

gnomAD frequency: 0.00001  dbSNP: rs80356865

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000049112	SCV000077125	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 245 of the BRCA1 protein (p.Asp245Val). This variant is present in population databases (rs80356865, gnomAD 0.003%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 26843898, 27495310). ClinVar contains an entry for this variant (Variation ID: 55682). 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 with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 23867111). 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.
Ambry Genetics	RCV000129392	SCV000184158	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-30	criteria provided, single submitter	clinical testing	The p.D245V variant (also known as c.734A>T), located in coding exon 9 of the BRCA1 gene, results from an A to T substitution at nucleotide position 734. The aspartic acid at codon 245 is replaced by valine, an amino acid with highly dissimilar properties. This alteration was identified in cohorts of women diagnosed with breast and/or ovarian cancer (Wojcik P et al. Hered Cancer Clin Pract, 2016 Feb;14:5; Foglietta J et al. Genes (Basel), 2020 Aug;11:). Another study reported this variant in a cohort of Norwegian individuals with family history of breast and/or ovarian cancer and classified it as a variant of uncertain significance (Jarhelle E et al. Fam. Cancer, 2017 01;16:1-16). This variant performed similar to wild type in a DNA interstrand crosslink (ICL) repair assay in BRCA1-deficient mouse embryonic stem cells expressing the human mutant BRCA1 c.734A>T cDNA and it was classified as neutral (Bouwman P et al. Cancer Discov, 2013 Oct;3:1142-55). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000766561	SCV000210086	uncertain significance	not provided	2022-09-22	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Published functional studies demonstrate no damaging effect (Bouwman et al., 2013); Also known as 853A>T; Observed in individuals with a personal and/or family history of breast and/or ovarian cancer (Jarhelle et al., 2016; Wojcik et al., 2016; Foglietta et al., 2020); This variant is associated with the following publications: (PMID: 27495310, 26843898, 22703879, 32806537, 31131967, 9926942, 9582019, 9788437, 20215511, 23867111)
Counsyl	RCV000112778	SCV000488015	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2015-12-16	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000766561	SCV000600436	uncertain significance	not provided	2023-06-01	criteria provided, single submitter	clinical testing	In the published literature, the variant has been reported in individuals with personal or family history of breast or ovarian cancer (PMID: 32806537 (2020), 27495310 (2016), 26843898 (2016), 25415331 (2014)). In a large-scale breast cancer association study, the variant was observed in individuals with breast cancer as well as in an unaffected individual (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA1)). A functional study has reported that this variant does not have a deleterious effect on BRCA1 protein function (PMID: 23867111 (2013)). The frequency of this variant in the general population, 0.000027 (3/113104 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Color Diagnostics, LLC DBA Color Health	RCV000129392	SCV001358887	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-11	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with valine at codon 245 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 shown this variant has neutral effect on DNA interstrand crosslink (ICL) repair (PMID: 23867111). This variant has been reported in multiple individuals affected with breast or ovarian cancer, as well as one unaffected individual (PMID: 26843898, 32806537, 33471991; LOVD DB-ID: BRCA1_001285) and an individual with family history of breast or ovarian cancer (PMID: 27495310). This variant has been identified in 3/250038 chromosomes 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001201209	SCV001372291	uncertain significance	not specified	2020-06-09	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.734A>T (p.Asp245Val) 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 allele was found at a frequency of 1.2e-05 in 250038 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.734A>T has been reported in the literature in patients with a family history or women diagnosed with breast or ovarian cancer (Jarhelle_2016, Wojcik_2016). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. In a cDNA-based functional assay, to classify the BRCA1 VUSs based on their ability of functionally complement BRCA1-deficient mouse embryonic stem cells, the variant was found to be neutral (Bouwman_2013). Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000129392	SCV003847981	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).
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112778	SCV000145672	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-06-20	no assertion criteria provided	clinical testing
Department of Medical Genetics, University Hospital of North Norway	RCV000112778	SCV000301429	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2016-05-01	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000766561	SCV001951938	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000766561	SCV001975134	uncertain significance	not provided		no assertion criteria provided	clinical testing