rs80359254
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_000059.4(BRCA2):āc.9934A>Gā(p.Ile3312Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,614,244 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
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.9934A>G | p.Ile3312Val | missense_variant | 27/27 | ENST00000380152.8 | NP_000050.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.9934A>G | p.Ile3312Val | missense_variant | 27/27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
BRCA2 | ENST00000530893.7 | c.9565A>G | p.Ile3189Val | missense_variant | 27/27 | 1 | ENSP00000499438.2 | |||
BRCA2 | ENST00000614259.2 | n.*1992A>G | non_coding_transcript_exon_variant | 26/26 | 2 | ENSP00000506251.1 | ||||
BRCA2 | ENST00000614259.2 | n.*1992A>G | 3_prime_UTR_variant | 26/26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152254Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251266Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135806
GnomAD4 exome AF: 0.0000144 AC: 21AN: 1461872Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13AN XY: 727234
GnomAD4 genome AF: 0.00000656 AC: 1AN: 152372Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74506
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:4Benign:1
Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 20, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jun 06, 2023 | This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 3312 of the BRCA2 protein (p.Ile3312Val). This variant is present in population databases (rs80359254, gnomAD 0.003%). This missense change has been observed in individual(s) with a personal or family history of breast or ovarian cancer (PMID: 18779604, 27124784, 31273614). ClinVar contains an entry for this variant (Variation ID: 38265). . 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 - |
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | Dec 23, 2003 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Jan 24, 2007 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jan 27, 2016 | - - |
Hereditary cancer-predisposing syndrome Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 19, 2024 | 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. - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 17, 2016 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 01, 2024 | Variant summary: BRCA2 c.9934A>G (p.Ile3312Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251266 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.9934A>G has been reported in the literature in individuals affected with breast cancer (e.g. Park_2016, Gervas_2019, Tariq_2021, Onsekiz_2021, Senturk_2021, Yao_2022) and premature ovarian insufficiency (e.g. Yilmaz_2016), without strong evidence for causality. 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. The following publications have been ascertained in the context of this evaluation (PMID: 31273614, 34658299, 27124784, 34828379, 28422718, 33773534, 35864222, 27403073). ClinVar contains an entry for this variant (Variation ID: 38265). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
BRCA2-related disorder Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 26, 2024 | The BRCA2 c.9934A>G variant is predicted to result in the amino acid substitution p.Ile3312Val. This variant has been reported as a variant of uncertain significance in several individuals with a personal history of breast and/or ovarian cancer (Tariq H et al 2021. PubMed ID: 33773534; Gervas P et al 2019. PubMed ID: 31273614; Senturk et al. 2021. PubMed ID: 34828379; Supp. Table 2 Yao et al 2022. PubMed ID: 35864222). This variant is reported in 0.0026% of alleles in individuals of European (non-Finnish) descent in gnomAD and has conflicting interpretations of likely benign and uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/38265/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 24, 2024 | Observed in individuals with personal and/or family history of breast and/or ovarian cancer (PMID: 18779604, 27124784, 31273614, 33471991, 34658299, 34828379, 33773534, 35864222); In silico analysis indicates that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 10162A>G; This variant is associated with the following publications: (PMID: 27403073, 20435227, 16011303, 18779604, 16683254, 27124784, 31273614, 34658299, 10733923, 33471991, 34828379, 28422718, 35864222, 33773534) - |
Hereditary breast ovarian cancer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 3312 of the BRCA2 protein (p.Ile3312Val). This variant is present in population databases (rs80359254, gnomAD 0.003%). This missense change has been observed in individual(s) with a personal or family history of breast or ovarian cancer (PMID: 18779604, 27124784, 31273614, 33773534, 34828379). ClinVar contains an entry for this variant (Variation ID: 38265). 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 BRCA2 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