13-32346855-G-T
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_000059.4(BRCA2):c.6966G>T(p.Met2322Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,609,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_000059.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.6966G>T | p.Met2322Ile | missense_variant | Exon 13 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
BRCA2 | ENST00000530893.7 | c.6597G>T | p.Met2199Ile | missense_variant | Exon 13 of 27 | 1 | ENSP00000499438.2 | |||
BRCA2 | ENST00000614259.2 | n.6966G>T | non_coding_transcript_exon_variant | Exon 12 of 26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152030Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000400 AC: 1AN: 250028Hom.: 0 AF XY: 0.00000740 AC XY: 1AN XY: 135198
GnomAD4 exome AF: 6.86e-7 AC: 1AN: 1457786Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1AN XY: 725216
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152030Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74262
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:3
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This missense variant replaces methionine with isoleucine at codon 2322 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 24824029, 26898890). This variant has been identified in 1/250028 chromosomes 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. -
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Hereditary cancer-predisposing syndrome Uncertain:3
This missense variant replaces methionine with isoleucine at codon 2322 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 24824029, 26898890). This variant has been identified in 1/250028 chromosomes 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. -
The p.M2322I variant (also known as c.6966G>T), located in coding exon 12 of the BRCA2 gene, results from a G to T substitution at nucleotide position 6966. The methionine at codon 2322 is replaced by isoleucine, an amino acid with highly similar properties. This alteration has been reported in multiple breast cancer patients (Cochran RL et al. Hum. Pathol., 2014 Jul;45:1546-50; Caminsky NG et al. Hum. Mutat., 2016 07;37:640-52). 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. -
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not provided Uncertain:2
The BRCA2 c.6966G>T (p.Met2322Ile) variant has been reported in the published literature in individuals with breast and/or ovarian cancer (PMIDs: 34326862 (2021), 26898890 (2016), 24824029 (2014)). One experimental study on mouse cells characterizes the variant as functional with no impact on cell viability or DNA damage sensitivity (PMID: 37713444 (2023)), however, additional studies are needed to confirm the variant's effect on BRCA2 protein function. The frequency of this variant in the general population, 0.000004 (1/250028 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. -
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 7194G>T; Observed in individuals with breast cancer (Cochran et al., 2014; Caminsky et al., 2016); This variant is associated with the following publications: (PMID: 24824029, 26898890) -
not specified Uncertain:1
Variant summary: BRCA2 c.6966G>T (p.Met2322Ile) 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 4e-06 in 250028 control chromosomes. c.6966G>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example: Cochran_2014, Caminsky_2016). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters have assessed the variant since 2014: all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -
Familial cancer of breast Uncertain:1
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Familial cancer of breast;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1
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Hereditary breast ovarian cancer syndrome Uncertain:1
This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 2322 of the BRCA2 protein (p.Met2322Ile). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 24824029, 26898890, 34326862). ClinVar contains an entry for this variant (Variation ID: 52229). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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