chr13-32362591-G-T
Variant summary
Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_000059.4(BRCA2):c.7874G>T(p.Arg2625Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,802 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R2625K) has been classified as Uncertain significance.
Frequency
Consequence
NM_000059.4 missense
Scores
Clinical Significance
Conservation
Publications
- breast-ovarian cancer, familial, susceptibility to, 2Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
- Fanconi anemia complementation group D1Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
- pancreatic cancer, susceptibility to, 2Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
- sarcomaInheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
- hereditary breast ovarian cancer syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Fanconi anemiaInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- medulloblastomaInheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
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ACMG classification
Our verdict: Likely_pathogenic. The variant received 6 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.7874G>T | p.Arg2625Ile | missense_variant | Exon 17 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
BRCA2 | ENST00000530893.7 | c.7505G>T | p.Arg2502Ile | missense_variant | Exon 17 of 27 | 1 | ENSP00000499438.2 | |||
BRCA2 | ENST00000614259.2 | n.7882G>T | non_coding_transcript_exon_variant | Exon 16 of 26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461802Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 727204 show subpopulations
Age Distribution
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:1Uncertain:1
This missense variant replaces arginine with isoleucine at codon 2625 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant impairs homology-directed DNA repair (PMID: 33609447). This variant has been reported in an individual affected with prostate cancer (PMID: 31874108). In a large breast cancer case-control study conducted by the BRIDGES consortium, this variant was reported in 2/60466 cases and 1/53461 unaffected controls (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_008629). This variant has not been identified 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. -
The p.R2625I variant (also known as c.7874G>T), located in coding exon 16 of the BRCA2 gene, results from a G to T substitution at nucleotide position 7874. The arginine at codon 2625 is replaced by isoleucine, an amino acid with similar properties. This variant was non-functional in a homology-directed DNA repair (HDR) assay (Ambry internal data). In addition, this variant was reported in 2/60,466 breast cancer cases and in 1/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This alteration is also predicted to destabilize the local structure and disrupt the protein binding ability of BRCA2 (Yang H et al. Science 2002 Sep;297:1837-48; Marston NJ et al. Mol. Cell. Biol. 1999 Jul;19:4633-42; Ambry internal data). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Hereditary breast ovarian cancer syndrome Uncertain:2
This sequence change replaces arginine, which is basic and polar, with isoleucine, which is neutral and non-polar, at codon 2625 of the BRCA2 protein (p.Arg2625Ile). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 419217). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 33609447) indicates that this missense variant is expected to disrupt BRCA2 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA2 function (PMID: 35736817). 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. -
According to the ClinGen ENIGMA BRCA2 v1.0.0 criteria we chose these criteria: PS3 (strong pathogenic): ClinGen BRCA2 Table 9: Richardson 2021 (PMID:33609447) - Damaging, PM2 (supporting pathogenic): not in gnomAD -
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1
This missense variant replaces arginine with isoleucine at codon 2625 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant impairs homology-directed DNA repair (PMID: 33609447). In a large breast cancer case-control study conducted by the BRIDGES consortium, this variant was reported in 2/60466 cases and 1/53461 unaffected controls (p-value=1; Leiden Open Variation Database DB-ID BRCA2_008629) (PMID: 33471991). This variant has not been identified 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:1
This variant is denoted BRCA2 c.7874G>T at the cDNA level, p.Arg2625Ile (R2625I) at the protein level, and results in the change of an Arginine to an Isoleucine (AGA>ATA). Using alternate nomenclature, this variant would be defined as BRCA2 8102G>T. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Arg2625Ile 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 Arginine and Isoleucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Arg2625Ile occurs at a position where amino acids with properties similar to Arginine are tolerated across species and is located in the DNA-binding domain (Borg 2010). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether BRCA2 Arg2625Ile is pathogenic or benign. We consider it to be a variant of uncertain significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at