13-32340868-GT-CG

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000059.4(BRCA2):​c.6513_6514delGTinsCG​(p.Ser2172Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V2171V) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

BRCA2
NM_000059.4 missense

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 0.620
Variant links:
Genes affected
BRCA2 (HGNC:1101): (BRCA2 DNA repair associated) Inherited mutations in BRCA1 and this gene, BRCA2, confer increased lifetime risk of developing breast or ovarian cancer. Both BRCA1 and BRCA2 are involved in maintenance of genome stability, specifically the homologous recombination pathway for double-strand DNA repair. The largest exon in both genes is exon 11, which harbors the most important and frequent mutations in breast cancer patients. The BRCA2 gene was found on chromosome 13q12.3 in human. The BRCA2 protein contains several copies of a 70 aa motif called the BRC motif, and these motifs mediate binding to the RAD51 recombinase which functions in DNA repair. BRCA2 is considered a tumor suppressor gene, as tumors with BRCA2 mutations generally exhibit loss of heterozygosity (LOH) of the wild-type allele. [provided by RefSeq, May 2020]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
BRCA2NM_000059.4 linkc.6513_6514delGTinsCG p.Ser2172Ala missense_variant ENST00000380152.8 NP_000050.3 P51587

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
BRCA2ENST00000380152.8 linkc.6513_6514delGTinsCG p.Ser2172Ala missense_variant 5 NM_000059.4 ENSP00000369497.3 P51587
BRCA2ENST00000530893.7 linkc.6144_6145delGTinsCG p.Ser2049Ala missense_variant 1 ENSP00000499438.2 A0A590UJI7
BRCA2ENST00000614259.2 linkn.6513_6514delGTinsCG non_coding_transcript_exon_variant Exon 10 of 26 2 ENSP00000506251.1 A0A7P0TAP7

Frequencies

GnomAD3 genomes
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2Benign:1
Mar 23, 2023
University of Washington Department of Laboratory Medicine, University of Washington
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: curation

Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -

Mar 06, 2024
Color Diagnostics, LLC DBA Color Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This missense variant replaces serine with alanine at codon 2172 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. 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. -

Feb 26, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.6513_6514delGTinsCG variant (also known as p.S2172A), located in coding exon 10 of the BRCA2 gene, results from an in-frame deletion of GT and insertion of CG at nucleotide positions 6513 to 6514. This results in the substitution of the serine residue for an alanine residue at codon 2172, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be neutral by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the available evidence, the clinical significance of this variant remains unclear. -

not specified Uncertain:1
Feb 19, 2018
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: The BRCA2 c.6513_6514delinsCG (p.Ser2172Ala) variant involves the alteration of a dinucleotide non-conserved sequence (GT>CG). Five out of five in silico analyses predict a benign outcome. However, these predictions have yet to be functionally assessed. This variant was not observed in 263870 control chromosomes (gnomAD). The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) classify the variant as "uncertain significance." Note, the single nucleotide change, c.6514T>G, causes the same missense change and has been reported by a clinical diagnostic laboratory (ClinVar submission) and a reputable database as "uncertain significance." Based on the available evidence, the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available. -

not provided Uncertain:1
Apr 15, 2019
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Not observed in large population cohorts (Lek et al., 2016) -

Hereditary breast ovarian cancer syndrome Uncertain:1
Dec 22, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 2172 of the BRCA2 protein (p.Ser2172Ala). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. 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: 419761). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Not Available". The alanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1064794089; hg19: chr13-32915005; API