17-43094642-T-G
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4BP6
The NM_007294.4(BRCA1):āc.889A>Cā(p.Met297Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M297I) has been classified as Benign.
Frequency
Consequence
NM_007294.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461874Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 727236
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:2Benign:1
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PM2(Supporting)+BP1(Strong) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042) -
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Hereditary cancer-predisposing syndrome Uncertain:2Benign:1
The p.M297L variant (also known as c.889A>C), located in coding exon 9 of the BRCA1 gene, results from an A to C substitution at nucleotide position 889. The methionine at codon 297 is replaced by leucine, an amino acid with highly similar properties. This alteration was reported in trans with a BRCA1 pathogenic mutation based on haplotype analysis in a patient with breast and/or ovarian cancer who underwent clinical genetic testing, and was classified as a variant of unknown significance (Judkins T et al. Cancer Res. 2005 Nov;65(21):10096-103). In a study of 1854 high-risk breast/ovarian cancer families in Italy, this alteration was detected in one family (Azzollini J et al. Eur. J. Intern. Med., 2016 Jul;32:65-71). This alteration was also observed in 1 of 1045 Italian patients with breast and/or ovarian cancer fulfilling established criteria for HBOC genetic testing (Zuntini R et al. Front Genet, 2018 Sep;9:378). 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. -
Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -
This missense variant replaces methionine with leucine 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 been reported in at least one individual affected with breast cancer and one suspected hereditary breast and ovarian cancer family (PMID: 27062684, 30254663, 32380732, 34178674). 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. -
not specified Uncertain:1Benign:1
Variant summary: BRCA1 c.889A>C (p.Met297Leu) results in a conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251274 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.889A>C has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome, without strong evidence for causality (Azzollini_2016, Fanale_2021, Zuntini_2018 ). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. 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: 27062684, 34178674, 30254663). ClinVar contains an entry for this variant (Variation ID: 55741). Based on the evidence outlined above, the variant was classified as uncertain significance. -
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not provided Uncertain:1
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 1008A>C; Observed in individuals with breast and/or ovarian cancer (Azzollini et al., 2016; Zuntini et al., 2018; Fanale et al., 2021); This variant is associated with the following publications: (PMID: 31131967, 27062684, 16267036, 15235020, 34178674, 30254663, 20215511, 15343273, 9788437, 9926942, 9582019) -
Hereditary breast ovarian cancer syndrome Uncertain:1
This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 297 of the BRCA1 protein (p.Met297Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of BRCA1-related conditions (PMID: 15235020, 27062684, 30254663, 34178674). ClinVar contains an entry for this variant (Variation ID: 55741). 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%. 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at