rs80359227
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_000059.4(BRCA2):āc.9583A>Gā(p.Thr3195Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000867 in 1,614,018 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. 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 -5 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.9583A>G | p.Thr3195Ala | missense_variant | Exon 26 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
BRCA2 | ENST00000530893.7 | c.9214A>G | p.Thr3072Ala | missense_variant | Exon 26 of 27 | 1 | ENSP00000499438.2 | |||
BRCA2 | ENST00000614259.2 | n.*1641A>G | non_coding_transcript_exon_variant | Exon 25 of 26 | 2 | ENSP00000506251.1 | ||||
BRCA2 | ENST00000614259.2 | n.*1641A>G | 3_prime_UTR_variant | Exon 25 of 26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152212Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251412Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135876
GnomAD4 exome AF: 0.00000889 AC: 13AN: 1461806Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7AN XY: 727212
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152212Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74362
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:2Benign:2
Likely benign, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | May 01, 2012 | - - |
Benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Apr 03, 2023 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | Feb 20, 2004 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Dec 10, 2015 | - - |
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 05, 2024 | Variant summary: BRCA2 c.9583A>G (p.Thr3195Ala) results in a non-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 1.2e-05 in 251412 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.9583A>G has been reported in the literature in individuals affected with breast and/or ovarian cancer (e.g. Simard_2007, Dutil_2019, Santonocito_2020). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. A recent study examining variants of uncertain significance in BRCA1/2, the French national COVAR (cosegregation variant) study, classified the variant as likely benign/benign based on variant cosegregation analyses and segregation data, however the detailed data was not available for review (Caputo_2021). 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: 16905680, 23704879, 28726806, 34597585, 31780696, 32438681). ClinVar contains an entry for this variant (Variation ID: 52872). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 29, 2018 | The BRCA2 c.9583A>G; p.Thr3195Ala variant (rs80359227), is reported in the literature in at least one individual with a family history of breast and/or ovarian cancer (Simard 2007). This variant is reported as uncertain significance/likely benign by multiple laboratories in ClinVar (Variation ID: 52872), and is only observed on three alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The threonine at codon 3195 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of the p.Thr3195Ala variant is uncertain at this time. References: Simard J et al. Evaluation of BRCA1 and BRCA2 mutation prevalence, risk prediction models and a multistep testing approach in French-Canadian families with high risk of breast and ovarian cancer. J Med Genet. 2007 Feb;44(2):107-21. - |
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Dec 22, 2023 | The BRCA2 c.9583A>G (p.Thr3195Ala) variant has been reported in the published literature in individuals with a personal or family history of breast and/or ovarian cancer (PMIDs: 16905680 (2007), 32438681 (2020), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared)). A multifactorial analysis study classified this variant as a variant of uncertain significance (PMID: 31131967 (2019)). The frequency of this variant in the general population, 0.000012 (3/251412 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 predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | May 21, 2019 | This variant is associated with the following publications: (PMID: 16905680, 25348012, 26295337, 23704879, 30212499, 28726806) - |
Hereditary cancer-predisposing syndrome Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 07, 2018 | 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. - |
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 09, 2017 | - - |
Hereditary breast ovarian cancer syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 19, 2025 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at