13-32346895-C-T
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM5BP4_StrongBP6
The NM_000059.4(BRCA2):c.7006C>T(p.Arg2336Cys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000181 in 1,604,296 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/21 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2336H) has been classified as Pathogenic.
Frequency
Consequence
NM_000059.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 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.7006C>T | p.Arg2336Cys | missense_variant, splice_region_variant | Exon 13 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
BRCA2 | ENST00000530893.7 | c.6637C>T | p.Arg2213Cys | missense_variant, splice_region_variant | Exon 13 of 27 | 1 | ENSP00000499438.2 | |||
BRCA2 | ENST00000614259.2 | n.7006C>T | splice_region_variant, non_coding_transcript_exon_variant | Exon 12 of 26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes AF: 0.0000855 AC: 13AN: 152018Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000807 AC: 2AN: 247890Hom.: 0 AF XY: 0.0000149 AC XY: 2AN XY: 134068
GnomAD4 exome AF: 0.0000110 AC: 16AN: 1452160Hom.: 0 Cov.: 29 AF XY: 0.0000125 AC XY: 9AN XY: 722552
GnomAD4 genome AF: 0.0000854 AC: 13AN: 152136Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6AN XY: 74372
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:3
This missense variant replaces arginine with cysteine at codon 2336 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 a breast cancer case-control meta-analysis in 1/60463 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_005905) and in families suspected of being affected with hereditary breast and ovarian cancer (PMID: 22366370, 29161300). This variant has been identified in 4/279248 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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not provided Uncertain:2Benign:1
Observed in individuals with a personal or family history of breast and/or ovarian cancer (Levanat et al., 2012; Alemar et al., 2017); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 7234C>T; This variant is associated with the following publications: (PMID: 31143303, 29541205, 29161300, 22366370, 32297440, 37129948, 32467295) -
The BRCA2 c.7006C>T (p.Arg2336Cys) variant has been reported in the published literature in individuals affected with breast and/or ovarian cancer (PMID: 22366370 (2012), 29161300 (2017), 33471991 (2021), 38509102 (2024)). The variant has also been reported in an unaffected individual (PMID: 32467295 (2020)). Splicing studies have shown that this variant results in normal splicing patterns and unaltered transcripts (PMID: 31143303 (2019)). The frequency of this variant in the general population, 0.00012 (3/24854 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. -
BRCA2: BP4, BS1:Supporting -
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
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. -
This missense variant replaces arginine with cysteine at codon 2336 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 a breast cancer case-control meta-analysis in 1/60463 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_005905) and in families suspected of being affected with hereditary breast and ovarian cancer (PMID: 22366370, 29161300). This variant has been identified in 4/279248 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. -
not specified Uncertain:1
Variant summary: BRCA2 c.7006C>T (p.Arg2336Cys) 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. Consensus agreement among computation tools predict no significant impact on normal splicing. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Wangensteen_2019). The variant allele was found at a frequency of 1.8e-05 in 1604526 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (1.8e-05 vs 0.00075), allowing no conclusion about variant significance. c.7006C>T has been reported in the literature in individuals with a personal and/or family history of Hereditary Breast and Ovarian Cancer and pancreatic ductal adenocarcinoma (Levanat_2012, Alemar_2017, Militello_2023, Bhai_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrence with another pathogenic variant has been reported at our laboratory, BRCA1 c.5324T>G(p.Met1775Arg), providing supporting evidence for a benign role. At least one publication reports experimental evidence that this variant has no impact on protein function (Sahu_2023). The following publications have been ascertained in the context of this evaluation (PMID: 29161300, 34326862, 18844490, 22366370, 37725113, 37713444, 31143303). ClinVar contains an entry for this variant (Variation ID: 96845). 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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BRCA2-related disorder Uncertain:1
The BRCA2 c.7006C>T variant is predicted to result in the amino acid substitution p.Arg2336Cys. This variant was reported in individuals with a personal or family history of breast and ovarian cancer, but family or functional studies were not reported to help assess the pathogenicity of this variant (Levanat et al. 2012. PubMed ID: 22366370; Alemar et al. 2017. PubMed ID: 29161300). In vitro splicing studies found that this variant did not alter splicing (Wangensteen T et al 2019. PubMed ID: 31143303). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD and is interpreted as uncertain significance by the vast majority of submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/96845/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Hereditary breast ovarian cancer syndrome Uncertain:1
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 2336 of the BRCA2 protein (p.Arg2336Cys). This variant is present in population databases (rs431825347, gnomAD 0.01%). This missense change has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 22366370; internal data). This missense change has been observed to co-occur in individuals with a different variant in BRCA2 that has been determined to be pathogenic (internal data), but the significance of this finding is unclear. ClinVar contains an entry for this variant (Variation ID: 96845). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The cysteine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (PMID: 31143303; internal data). 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. -
Ovarian cancer Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at