Submissions for variant NM_007294.4(BRCA1):c.889A>G (p.Met297Val)

dbSNP: rs80357196

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131947	SCV000187004	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-22	criteria provided, single submitter	clinical testing	The p.M297V variant (also known as c.889A>G), located in coding exon 9 of the BRCA1 gene, results from an A to G substitution at nucleotide position 889. The methionine at codon 297 is replaced by valine, an amino acid with highly similar properties. In a functional study, the M297V variant was found to make the BRCA1 protein more prone to proteasome-mediated degradation (Hovland HN et al. Genes (Basel), 2023 Jan;14). 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.
GeneDx	RCV000486631	SCV000565727	uncertain significance	not provided	2016-09-15	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.889A>G at the cDNA level, p.Met297Val (M297V) at the protein level, and results in the change of a Methionine to a Valine (ATG>GTG). Using alternate nomenclature, this variant would be defined as BRCA1 1008A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Met297Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Methionine and Valine share similar properties, this is considered a conservative amino acid substitution. BRCA1 Met297Val occurs at a position where amino acids with properties similar to Methionine are tolerated across species and is located in a region known to interact with multiple proteins (Paul 2014). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether BRCA1 Met297Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000549625	SCV000636082	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-07-28	criteria provided, single submitter	clinical testing	This variant is present in population databases (rs80357196, gnomAD 0.006%). This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 297 of the BRCA1 protein (p.Met297Val). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 142628). 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. Studies have shown that this missense change alters BRCA1 gene expression (PMID: 36833189). 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	RCV000239288	SCV000785223	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2017-06-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004562302	SCV001360674	uncertain significance	not specified	2023-11-20	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.889A>G (p.Met297Val) results in a 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 4e-06 in 251274 control chromosomes. c.889A>G was reported as Likely benign and VUS changes in two diagnostic genetic laboratories in Norway, respectively (Hovland_2022), detailed clinical information however was not specified. In a large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), the variant was reported in 3/60466 cases, but was also found in 1/53461 controls (Dorling_2021 through LOVD). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in about 20% of normal protein levels with increased proteasome-mediated degradation in HEK293 cells (Hovland_2023). The following publications have been ascertained in the context of this evaluation (PMID: 34981296, 36833189, 20668451, 33471991). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=4, Likely benign, n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000131947	SCV003847870	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).
All of Us Research Program, National Institutes of Health	RCV000239288	SCV004818399	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2023-06-15	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with valine at codon 297 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251274 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.
Sharing Clinical Reports Project (SCRP)	RCV000239288	SCV000297626	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2011-12-21	no assertion criteria provided	clinical testing