Submissions for variant NM_007294.4(BRCA1):c.3091A>G (p.Ile1031Val)

dbSNP: rs786203979

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000168281	SCV000218953	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-06-23	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 188293). 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. 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. This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1031 of the BRCA1 protein (p.Ile1031Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with a personal or family history of breast and/or ovarian cancer (PMID: 31159747).
GeneKor MSA	RCV000708677	SCV000821922	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000708677	SCV001179812	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-16	criteria provided, single submitter	clinical testing	The p.I1031V variant (also known as c.3091A>G), located in coding exon 9 of the BRCA1 gene, results from an A to G substitution at nucleotide position 3091. The isoleucine at codon 1031 is replaced by valine, an amino acid with highly similar properties. This alteration has been reported in 2/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). This amino acid position is not 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000708677	SCV003849135	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).
PreventionGenetics, part of Exact Sciences	RCV004554741	SCV004104144	uncertain significance	BRCA1-related disorder	2023-08-01	criteria provided, single submitter	clinical testing	The BRCA1 c.3091A>G variant is predicted to result in the amino acid substitution p.Ile1031Val. This variant was reported in an individual with breast cancer (Table S5, Tsaousis et al. 2019. PubMed ID: 31159747). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. In ClinVar, this variant has been interpreted as uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/188293/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.