NM_007294.4:c.1772T>C
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4BP6
The NM_007294.4(BRCA1):āc.1772T>Cā(p.Ile591Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,684 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).
Frequency
Consequence
NM_007294.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000797 AC: 2AN: 251098Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135750
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461684Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1AN XY: 727138
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Benign:3
Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
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not provided Uncertain:2
The BRCA1 c.1772T>C (p.Ile591Thr) variant has been reported in the published literature in individuals affected with breast cancer (PMIDs: 37415649 (2023), 25777348 (2015), 22476429 (2012)) and gliobastomas (PMID: 26933808 (20016)). The frequency of this variant in the general population, 0.000008 (2/251098 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 conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
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Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1Benign:1
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Hereditary breast ovarian cancer syndrome Uncertain:1Benign:1
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not specified Benign:2
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Variant summary: BRCA1 c.1772T>C (p.Ile591Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. In addition, a report from the CAGI5 (fifth Critical Assessment of Genome Interpretation) challenge has classified this variant as likely benign in a prediction protocol that includes assessment of the impact of this variant on splicing and protein function using four sets of predictors (Padilla_2019, Cline_2019). The variant allele was found at a frequency of 8e-06 in 251098 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1772T>C has been reported in the literature in individuals with personal and/or family history of breast cancer and other tumor phenotype(s), however without supporting evidence for causality (e.g. Kurian_2008, Lu_2012, ElSaghir_2015, Xiu_2016, Boga_2023). In a large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), the variant was reported in 1/60466 cases, but was also found in 2/53461 controls (Dorling_2021, reported through LOVD). These reports 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. However, a large-scale study utilizing multifactorial probability model for quantitative analysis of BRCA1 and BRCA2 variants predicted this variant to be likely benign (Parsons_2019). The following publications have been ascertained in the context of this evaluation (PMID: 25777348, 18779604, 22476429, 15385441, 28439188, 26933808, 33471991, 37415649, 34981296, 31112341, 31294896, 31131967). ClinVar contains an entry for this variant (Variation ID: 54345). Based on the evidence outlined above, the variant was classified as likely benign. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at