rs1064793691
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_000059.4(BRCA2):c.8844T>G(p.Ile2948Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,544 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. I2948I) has been classified as Likely benign.
Frequency
Consequence
NM_000059.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.8844T>G | p.Ile2948Met | missense_variant | 22/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.8844T>G | p.Ile2948Met | missense_variant | 22/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461544Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727068
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 07, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 21, 2022 | The p.I2948M variant (also known as c.8844T>G), located in coding exon 21 of the BRCA2 gene, results from a T to G substitution at nucleotide position 8844. The isoleucine at codon 2948 is replaced by methionine, an amino acid with highly similar properties. This alteration was seen in 1/732 breast cancer patients, 0/189 colorectal cancer patients and 0/490 cancer-free elderly controls in a Turkish population (Akcay IM et al. Int J Cancer, 2021 01;148:285-295). 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. - |
Hereditary breast ovarian cancer syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Oct 31, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 06, 2019 | 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 419170). This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with methionine at codon 2948 of the BRCA2 protein (p.Ile2948Met). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and methionine. - |
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jun 06, 2023 | A variant of uncertain significance was detected in this sample . This sequence change replaces leucine with methionine at codon 2948 of the BRCA2 protein (p.Ile2948Met ) also known as c.8844T>G, which located in coding exon 22 of the BRCA2 gene(NM_000059.3), results from a T to G substitution at nucleotide position 8844. Since Isoleucine and Methionine share similar properties, this is considered a conservative amino acid substitution.This amino acid position Ile2948Met is not conserved and is located in the DNA-binding domain. This variant is not present in population databases (gnomAD ). This variant reported in ClinVar database (ID: 419170) . This alteration is predicted to be possibly pathogenic by SIFT , Otherwise , predicted to be tolerated by other in silico analysis.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 provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 01, 2015 | This variant is denoted BRCA2 c.8844T>G at the cDNA level, p.Ile2948Met (I2948M) at the protein level, and results in the change of an Isoleucine to a Methionine (ATT>ATG). Using alternate nomenclature, this variant would be defined as BRCA2 9072T>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Ile2948Met was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Isoleucine and Methionine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Ile2948Met occurs at a position that is not conserved and is located in the DNA-binding domain (Borg 2010). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BRCA2 Ile2948Met is pathogenic or benign. We consider it to be a variant of uncertain significance. - |
Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Feb 09, 2024 | ACMG codes applied following ENIGMA VCEP rules: BP4, PM2_SUP - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at