13-32357749-C-T
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6
The NM_000059.4(BRCA2):c.7625C>T(p.Thr2542Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000745 in 1,611,172 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T2542T) has been classified as Benign.
Frequency
Consequence
NM_000059.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.7625C>T | p.Thr2542Met | missense_variant | 16/27 | ENST00000380152.8 | NP_000050.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.7625C>T | p.Thr2542Met | missense_variant | 16/27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
BRCA2 | ENST00000530893.7 | c.7256C>T | p.Thr2419Met | missense_variant | 16/27 | 1 | ENSP00000499438.2 | |||
BRCA2 | ENST00000614259.2 | n.7625C>T | non_coding_transcript_exon_variant | 15/26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 151930Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250756Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135616
GnomAD4 exome AF: 0.00000754 AC: 11AN: 1459242Hom.: 0 Cov.: 31 AF XY: 0.00000551 AC XY: 4AN XY: 726086
GnomAD4 genome AF: 0.00000658 AC: 1AN: 151930Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74204
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | May 01, 2012 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRCA2 p.Thr2542Met variant was identified in a Turkmen (Iranian) individual with esophageal squamous cell carcinoma (Akbari 2008), and was also identified in the COSMIC database. The p.Thr2542 residue is not conserved in mammals and the variant amino acid methionine (Met) is present in chimp, macaque, rat, dog, cat and opossum, increasing the likelihood that this variant does not have clinical significance. In addition, Akbari (2008) notes that structural crystallography in the region of the variant shows that the p.Thr2542 residue does not have a special role in the secondary structure of the BRCA2 protein. Computational analyses (PolyPhen-2, SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance. - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 06, 2024 | Observed in patients with personal or family history of breast/ovarian cancer and in unaffected/cancer-free individuals (PMID: 16760289, 33471991, 32467295); 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 7853C>T; This variant is associated with the following publications: (PMID: 17724471, 22072316, 22425665, 16760289, 12228710, 33471991, 35464868, 29884841, 31853058, 32467295, 32947577) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Nov 05, 2024 | The BRCA2 c.7625C>T (p.Thr2542Met) variant has been reported in the published literature in individuals with esophageal squamous cell carcinoma (PMID: 17724471 (2008)), breast cancer (PMID: 30982232 (2019)), and as c.7625T>C in a homozygous individual with Fanconi Anemia (PMID: 32947577 (2021)). This variant has also been seen in reportedly healthy individuals (PMID: 32467295 (2020), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/)). Prediction models suggest this variant has a neutral impact on function (PMIDs: 29884841 (2019), 31853058 (2020)). The frequency of this variant in the general population, 0.000004 (1/250756 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:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 10, 2022 | This missense variant replaces threonine with methionine at codon 2542 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 with a personal or family history of breast or ovarian cancer, and in an individual affected with esophageal cancer (PMID: 16760289, 1772447, 30982232). In a large breast cancer case-control study conducted by the BRIDGES consortium, this variant was reported in 5/60466 cases and 3/53461 unaffected controls, showing inconclusive association with disease (OR= 1.474 (95%CI 0.352 to 6.167)); p-value= 0.731; Leiden Open Variation Database DB-ID BRCA2_008612) (PMID: 33471991). This variant has been identified in 1/250756 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. - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 09, 2017 | 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. - |
Hereditary breast ovarian cancer syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 24, 2023 | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 2542 of the BRCA2 protein (p.Thr2542Met). 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 cancer, esophageal squamous cell carcinoma, and/or Fanconi anemia (PMID: 17724471, 30982232, 32947577). ClinVar contains an entry for this variant (Variation ID: 96854). 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. - |
Likely benign, criteria provided, single submitter | clinical testing | National Health Laboratory Service, Universitas Academic Hospital and University of the Free State | Nov 16, 2021 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 27, 2023 | Variant summary: BRCA2 c.7625C>T (p.Thr2542Met) results in a non-conservative amino acid change located in the helical domain (IPR015252) of 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 4e-06 in 250756 control chromosomes (gnomAD v2.1). c.7625C>T has been reported in the literature in heterozygous state in two individuals affected with breast- and/or ovarian cancer (Capalbo_2006, Wang_2019), and in a 73-year-old individual with esophageal carcinoma (Akbari_2008), however it was also reported in two healthy controls (Dong_2021 and in the FLOSSIES database). In a recent large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), the variant was reported in 5/60466 cases, but was also found in 3/53461 controls (Dorling_2021, through LOVD). A recent study reported the variant in homozygous state in an infant affected with Fanconi Anemia, who was born from a consanguineous marriage, however no convincing evidence was provided that would confirm the pathogenic role of this variant, or would exclude the presence of other causative variants (Farah_2021). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as VUS (n=6) or likely benign (n=2). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
Medulloblastoma;C0040588:Tracheoesophageal fistula;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 | May 23, 2017 | - - |
BRCA2-related cancer predisposition Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Sep 23, 2024 | - - |
Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 10, 2024 | - - |
Hereditary cancer Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Mendelics | Sep 11, 2024 | This variant is considered likely benign or benign based on one or more of the following: it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease, and/or has normal protein function, and/or has lack of segregation with disease, and/or has been detected in co-occurrence with known pathogenic variant, and/or has lack of disease association in case-control studies, and/or is located in a region inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at