rs80358966
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3
The NM_000059.4(BRCA2):āc.7447A>Gā(p.Ser2483Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,452 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S2483N) has been classified as Likely benign.
Frequency
Consequence
NM_000059.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.7447A>G | p.Ser2483Gly | missense_variant | 15/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.7447A>G | p.Ser2483Gly | missense_variant | 15/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152198Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251306Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135832
GnomAD4 exome AF: 0.00000411 AC: 6AN: 1461254Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 726992
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152198Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74372
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:3
Uncertain significance, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Mar 02, 2020 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Aug 15, 2023 | This missense variant replaces serine with glycine at codon 2483 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). A functional study has reported that this variant does not impact BRCA2 function in Brca2-deficient mouse embryonic stem cells (PMID: 33293522). A RNA study reported that this variant resulted in 10% of transcripts with an in-frame partial deletion of exon 15 (resulting in the protein change Asp2479_Ser2483delinsGly). This variant has been reported in individuals affected with breast or ovarian cancer (PMID: 11979449, 12955716, 16685647, 21735045), an individual with breast/ovarian cancer or Lynch syndrome (PMID: 32522261) and an unaffected individual (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_000190). This variant has been identified in 4/251306 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 provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 28, 2023 | Published functional studies demonstrate that this variant results in cell survival similar to wild-type in assays evaluating ability to rescue BRCA2-null lethality and sensitivity to DNA damaging agents (Biswas et al., 2020); Published splicing studies demonstrate this variant results in slightly disrupted splicing with the majority of transcripts being full-length while only a minority of transcripts lacked the first 12 nucleotides of exon 15 (Fraile-Bethencourt et al., 2019; Montalban et al., 2019); In silico analysis supports a deleterious effect on splicing; 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 7675A>G; This variant is associated with the following publications: (PMID: 19043619, 21523855, 11979449, 12955716, 16685647, 26913838, 31191615, 12228710, 30472649, 32522261, 31396961, 21735045, 31343793, 33293522) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jun 14, 2023 | In the published literature, this variant has been reported in individuals with breast and/or ovarian cancer or Lynch syndrome (PMIDs: 11979449 (2002), 12955716 (2003), 16685647 (2006), 21735045 (2012), and 32522261 (2020)) and in an individual with Esophageal squamous carcinoma (PMID: 31396961 (2020)). Functional studies using cell survival and drug sensitivity assays showed that the variant is likely functional (PMID: 33293522 (2020)). In addition, other experimental studies reported that this variant resulted in only 10% of transcripts with an in-frame partial deletion of exon 15 while most of transcripts (90%) were full length (PMIDs: 31343793 (2019) and 31191615 (2019)). The frequency of this variant in the general population, 0.000087 (3/34572 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. - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 27, 2023 | This missense variant replaces serine with glycine at codon 2483 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). A functional study has reported that this variant does not impact BRCA2 function in Brca2-deficient mouse embryonic stem cells (PMID: 33293522). A RNA study reported that this variant resulted in 10% of transcripts with an in-frame partial deletion of exon 15 (resulting in the protein change Asp2479_Ser2483delinsGly). This variant has been reported in individuals affected with breast or ovarian cancer (PMID: 11979449, 12955716, 16685647, 21735045), an individual with breast/ovarian cancer or Lynch syndrome (PMID: 32522261) and an unaffected individual (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_000190). This variant has been identified in 4/251306 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 23, 2022 | The p.S2483G variant (also known as c.7447A>G), located in coding exon 14 of the BRCA2 gene, results from an A to G substitution at nucleotide position 7447. The serine at codon 2483 is replaced by glycine, an amino acid with similar properties. This variant has been reported in high risk breast cancer families and a high risk breast and ovarian cancer family (Osorio A et al. Int. J. Cancer. 2002 May;99:305-9; Weber F et al. Am. J. Hum. Genet. 2006 Jun;78:961-72; Menéndez M et al. Breast Cancer Res. Treat. 2012 Apr;132:979-92; Díez O et al. Hum. Mutat. 2003 Oct;22:301-12). One study found that this alteration results in incomplete use of this cryptic acceptor site, producing a transcript with the predicted in-frame deletion of 12 nucleotides in coding exon 14 (Fraile-Bethencourt E et al. Front Genet. 2019 May;10:503). However, other studies have found that this alteration does not result in a significant amount of aberrant splicing (Ambry internal data, Menéndez M et al. Breast Cancer Res. Treat. 2012 Apr;132:979-92). This amino acid position is poorly conserved in available vertebrate species. In addition, this amino acid change is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Hereditary breast ovarian cancer syndrome Uncertain:2
Uncertain significance, no assertion criteria provided | research | Hereditary Cancer Genetics group, Vall d'Hebron Institute of Oncology | Mar 01, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2024 | This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 2483 of the BRCA2 protein (p.Ser2483Gly). This variant is present in population databases (rs80358966, gnomAD 0.009%). This missense change has been observed in individual(s) with breast cancer, esophageal squamous cell carcinoma, and/or ovarian cancer (PMID: 11979449, 12955716, 21735045, 31396961). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 52334). 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%. Experimental studies have shown that this missense change does not substantially affect BRCA2 function (PMID: 33293522). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (PMID: 31191615, 31343793; Invitae). 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 27, 2022 | Variant summary: BRCA2 c.7447A>G (p.Ser2483Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. A computational method that produces a probabilistic likelihood ratio has predicted a neutral impact (Karchin_2008). 5/5 computational tools predict no significant impact on normal splicing at the canonical splice acceptor site although three tools predicted the creation of a new exonic acceptor site located 12 nucleotides downstream from the canonical splice acceptor site (Montalban_2019). At-least two studies reported a very low levels (10%) of transcript lacking 12 nucleotides from the 5' end of exon 15, while the majority of transcripts (90%) were full length (Montalban_2019, Fraile-Bethencourt_2019). However, the exact in-vivo consequences of these findings is not clear. The variant allele was found at a frequency of 1.6e-05 in 251306 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7447A>G has been reported in the literature in individuals from a Spanish family affected with breast cancer (Osorio_2002) that has been subsequently cited by others (Diez_2003, Montalban_2019) and in one case from a study of Esophageal squamous carcinoma in China (Ko_2020). Tumor analysis performed in the initial report from the Spanish family demonstrated retention of the wild-type allele and loss of the allele harbouring the variant confirming that the variant is not deleterious (Osorio_2002). Therefore, these report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function (Biswas_2020). These results showed "no damaging effect" of this variant in a mouse embryonic stem cell-based functional assay examining the ability to rescue the lethality of BRCA2 null mESC as well as sensitivity to six DNA damaging agents including ionizing radiation and a PARP inhibitor. This finding is consistent with the predominantly wild-type transcript pattern in the splicing assays summarized above. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. - |
Medulloblastoma;C0346153:Familial cancer of breast;C0376358:Malignant tumor of prostate;C1838457:Fanconi anemia complementation group D1;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2;C2751641:Glioma susceptibility 3;C3150546:Pancreatic cancer, susceptibility to, 2;CN033288:Wilms tumor 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 05, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at