13-32333247-T-G
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6
The NM_000059.4(BRCA2):āc.1769T>Gā(p.Phe590Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000062 in 1,611,694 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000059.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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BRCA2 | ENST00000380152.8 | c.1769T>G | p.Phe590Cys | missense_variant | Exon 10 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
BRCA2 | ENST00000530893.7 | c.1400T>G | p.Phe467Cys | missense_variant | Exon 10 of 27 | 1 | ENSP00000499438.2 | |||
BRCA2 | ENST00000614259.2 | n.1769T>G | non_coding_transcript_exon_variant | Exon 9 of 26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152128Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000121 AC: 3AN: 248932Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 134758
GnomAD4 exome AF: 0.00000548 AC: 8AN: 1459566Hom.: 0 Cov.: 35 AF XY: 0.00000689 AC XY: 5AN XY: 726122
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152128Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74288
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:2Benign:2
BS3(Strong)+BP1(Strong)+BP5(Supporting) 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:1Benign:3
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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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Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -
not provided Uncertain:1Benign:1
In the published literature, this variant has been reported in individuals with breast cancer (PMID: 35402282 (2022), 34178674 (2021), 32854451 (2020)), and Cowden Syndrome/Cowden Syndrome-like Bannayan-Riley Ruvalcaba Syndrome (PMID: 29684080 (2018)). Published functional studies have reported that this variant does not have a deleterious effect on BRCA2 protein function (PMID: 29988080 (2018)). The frequency of this variant in the general population, 0.000012 (3/248932 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. -
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; A published in vitro functional assay suggests that this variant is able to rescue cell lethality (Mesman 2018); Observed in at least one individual with breast or ovarian cancer (Azzollini 2016); This variant is associated with the following publications: (PMID: 25348012, 11929857, 29988080, 24817641, 27062684, 32854451, 29684080) -
not specified Uncertain:1
Variant summary: BRCA2 c.1769T>G (p.Phe590Cys) 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 244108 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1769T>G has been reported in the literature in an individual affected with Hereditary Breast and Ovarian Cancer who was indicated to carry another pathogenic variant, although the variant was not specified (Azzollini_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in normal activity using multiple independent measures namely, complementation by BRCA2 variants of the cell lethal phenotype imposed by Cre-mediated loss of Brca2; HDR capacity, as measured by the repair of I-Sce1 induced double strand breaks (DSBs); and Cisplatin sensitivity of BRCA2 variants (Meman_2018). Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Breast and/or ovarian cancer Uncertain:1
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Hereditary breast ovarian cancer syndrome Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at