chr13-32337802-G-A
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_000059.4(BRCA2):c.3447G>A(p.Met1149Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,461,750 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1149L) has been classified as Likely benign.
Frequency
Consequence
NM_000059.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.3447G>A | p.Met1149Ile | missense_variant | 11/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.3447G>A | p.Met1149Ile | missense_variant | 11/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 250982Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135644
GnomAD4 exome AF: 0.0000109 AC: 16AN: 1461750Hom.: 0 Cov.: 35 AF XY: 0.0000124 AC XY: 9AN XY: 727176
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 16, 2023 | This missense variant replaces methionine with isoleucine at codon 1149 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 prostate cancer (PMID: 21952622, 31874108) or pancreatic cancer (PMID: 28767289, 32659497). In a large breast cancer case-control meta-analysis conducted by the BRIDGES consortium, this variant was reported in 3/60466 cases and 1/53461 unaffected controls (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001835). This variant has been identified in 1/250982 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 | Sep 09, 2022 | The p.M1149I variant (also known as c.3447G>A), located in coding exon 10 of the BRCA2 gene, results from a G to A substitution at nucleotide position 3447. The methionine at codon 1149 is replaced by isoleucine, an amino acid with highly similar properties. This alteration has been reported in an Indonesian woman diagnosed with early-onset breast cancer and in a patient diagnosed with sporadic pancreatic cancer at age 73y (Purnomosari D. et al. "Histopathological features of early onset Indonesian breast cancer pointing to BRCA1/2 germline mutations." Berita Kedokteran Masyarakat, Vol. 23, No. 3, September 2007; Shindo K et al. J Clin Oncol. 2017 Oct 20;35(30):3382-3390). In addition, this alteration was reported as being identified in a cohort of pancreatic ductal adenocarcinoma patients undergoing multigene panel testing (Hu H et al. J Am Coll Surg, 2020 11;231:527-535.e14), and in a cohort of prostate cancer patients who underwent screening for alterations in BRCA2 (Kote-Jarai Z et al. Br J Cancer, 2011 Oct;105:1230-4). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration 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. - |
Likely benign, criteria provided, single submitter | curation | University of Washington Department of Laboratory Medicine, University of Washington | Mar 23, 2023 | Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). - |
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 13, 2023 | This missense variant replaces methionine with isoleucine at codon 1149 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 prostate cancer (PMID: 21952622, 31874108) or pancreatic cancer (PMID: 28767289, 32659497). In a large breast cancer case-control meta-analysis conducted by the BRIDGES consortium, this variant was reported in 3/60466 cases and 1/53461 unaffected controls (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001835). This variant has been identified in 1/250982 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. - |
Breast and/or ovarian cancer Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Sep 27, 2021 | - - |
Fanconi anemia complementation group D1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 20, 2021 | - - |
Hereditary breast ovarian cancer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 27, 2023 | This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1149 of the BRCA2 protein (p.Met1149Ile). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with pancreatic cancer (PMID: 28767289, 32659497). ClinVar contains an entry for this variant (Variation ID: 233535). 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