chr13-32362543-G-T

Position:

• chr13-32362543-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000059.4(BRCA2):​c.7826G>T​(p.Gly2609Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 9.85

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.954
• PP5: Variant 13-32362543-G-T is Pathogenic according to our data. Variant chr13-32362543-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 232537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.7826G>T	p.Gly2609Val	missense_variant	17/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.7826G>T	p.Gly2609Val	missense_variant	17/27	5	NM_000059.4	ENSP00000369497	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 09, 2022	PM2, PS3 -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 05, 2024	This variant is denoted BRCA2 c.7826G>T at the cDNA level, p.Gly2609Val (G2609V) at the protein level, and results in the change of a Glycine to a Valine (GGT>GTT). Using alternate nomenclature, this variant would be defined as BRCA2 8054G>T. Functional assays interrogating homology directed repair demonstrated a pathogenic effect (Guidugli 2018). BRCA2 Gly2609Val was not observed in large population cohorts (Lek 2016). This variant is located in the DNA binding domain (Yang 2002). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Gly2609Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Sep 25, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 16, 2023	The p.G2609V variant (also known as c.7826G>T), located in coding exon 16 of the BRCA2 gene, results from a G to T substitution at nucleotide position 7826. The glycine at codon 2609 is replaced by valine, an amino acid with dissimilar properties. This alteration has demonstrated defective homology-directed repair (Guidugli L et al. Hum. Mutat. 2014 Feb;35:151-64; Guidugli L et al. Am. J. Hum. Genet. 2018 02;102(2):233-248; Hart SN et al. Genet. Med. 2019 01;21(1):71-80). This alteration is also predicted to strongly 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 variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly 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 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 30, 2023	This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2609 of the BRCA2 protein (p.Gly2609Val). 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: 232537). Advanced modeling performed at Invitae incorporating data from internal and/or published 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: 29394989, 29884841). This variant disrupts the p.Gly2609 amino acid residue in BRCA2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21990134, 23108138, 29394989, 29884841, 29988080). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	curation	Cancer Variant Interpretation Group UK, Institute of Cancer Research, London	Nov 23, 2018	Data used in classification: The frequency of this variant is 0/138,632 individuals (gnomAD) (PM2_mod). This variant is predicted deleterious on AlignGVGD (class: C65), SIFT (Deleterious), Polyphen2 HumVar (probably damaging) and CADD (28.5) (PP3_sup). The variant is in the DNA-binding domain of BRCA2 (PM1_sup). In the VarCall Bayesian statistical model for VUS classification using functional assay data (Guidugli et al Am J Hum Genet 2018; 102:233-248, Couch Lab), the variant has a probability of being deleterious of 0.997 and an overall classification of pathogenic. (PS3_strong). This variant is classified on ClinVar as Likely Pathogenic by accredited diagnostic USA laboratory Ambry Genetics, 2018. (PP5_sup). Data not used in classification: There are no additional reports of this variant in BIC or BRCA2 LOVD. -

Familial cancer of breast Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 14, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	27
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.4	N;N
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.76
MutPred		0.83		Gain of ubiquitination at K2613 (P = 0.107);Gain of ubiquitination at K2613 (P = 0.107);
MVP		0.99
MPC		0.18
ClinPred		0.99	D
GERP RS		5.7
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs80359009; hg19: chr13-32936680;