13-32394716-A-G

Variant names:

• chr13-32394716-A-G
• rs1060502443
• NM_000059.4:c.9284A>G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000059.4(BRCA2):​c.9284A>G​(p.Asp3095Gly) variant causes a missense change. 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D3095E) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 6.06

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 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-32394717-C-G is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.961
• PP5: Variant 13-32394716-A-G is Pathogenic according to our data. Variant chr13-32394716-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 409512.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.9284A>G	p.Asp3095Gly	missense_variant	Exon 25 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.9284A>G	p.Asp3095Gly	missense_variant	Exon 25 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.8915A>G	p.Asp2972Gly	missense_variant	Exon 25 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*1342A>G		non_coding_transcript_exon_variant	Exon 24 of 26	2		ENSP00000506251.1
BRCA2	ENST00000614259	n.*1342A>G		3_prime_UTR_variant	Exon 24 of 25	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary breast ovarian cancer syndrome Pathogenic:2

Nov 03, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRCA2 c.9284A>G (p.Asp3095Gly) results in a non-conservative amino acid change located in the 3rd oligonucleotide binding (OB) fold (IPR015188), which is part of the DNA-binding domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250672 control chromosomes (gnomAD). c.9284A>G has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g., Tung_2014, Dorling_2021). At least one publication reports experimental evidence evaluating an impact on protein function (e.g., Richardson_2021). The results of this study showed the variant to be non-functional in a homology directed repair (HDR) activity assay. HDR assays qualify as a recognized gold standard on the basis of updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) working group (PMID: 31892348). ClinGen SVI now recognizes benign functional evidence as sufficient for categorization as likely benign (PMID: 29300386). The following publications have been ascertained in the context of this evaluation (PMID: 33609447, 25186627, 33471991). Three submitters have reported clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as pathogenic (n = 1), likely pathogenic (n = 1), and uncertain significance (n = 1). Additionally, a different missense variant affecting the same codon, namely c.9285C>G (p.Asp3095Glu), has been classified as pathogenic by our lab.Based on the evidence outlined above, the variant was classified as pathogenic. -

Dec 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 3095 of the BRCA2 protein (p.Asp3095Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 409512). 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%. This variant disrupts the p.Asp3095 amino acid residue in BRCA2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18451181, 18951446, 22678057). 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. -

not provided Pathogenic:1

May 01, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.9284A>G; p.Asp3095Gly variant (rs1060502443, ClinVar variation ID: 409512) is reported in the literature in one individual affected with breast cancer (Tung 2015). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Additionally, other variants at this codon (c.9285C>G, p.Asp3095Glu) have been reported in individuals with cancer and are considered pathogenic (Guidugli 2013). In vitro functional analyses demonstrate significantly reduced homology-directed repair activity similar to other pathogenic variants (Richardson 2021). This variant is located within the BRCA2 DNA binding domain (aa2481-3186), but computational analyses predict that this variant is uninformative (BayesDel: 0.201). Based on available information, this variant is considered to be likely pathogenic. References: Guidugli L et al. A classification model for BRCA2 DNA binding domain missense variants based on homology-directed repair activity. Cancer Res. 2013 Jan 1;73(1):265-75. PMID: 23108138. Richardson ME et al. Strong functional data for pathogenicity or neutrality classify BRCA2 DNA-binding-domain variants of uncertain significance. Am J Hum Genet. 2021 Mar 4;108(3):458-468. PMID: 33609447. -

Hereditary cancer-predisposing syndrome Pathogenic:1

May 26, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D3095G pathogenic mutation (also known as c.9284A>G), located in coding exon 24 of the BRCA2 gene, results from an A to G substitution at nucleotide position 9284. The aspartic acid at codon 3095 is replaced by glycine, an amino acid with very few similar properties. A close-match alteration at this same codon, p.D3095E, is considered pathogenic (Ambry internal data). This alteration was non-functional in a homology-directed DNA repair (HDR) assay (Ambry internal data). This variant segregated with breast cancer in several members of the same family (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD) (Lek M et al. Nature, 2016 08;536:285-91).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 considered a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Uncertain	26
DANN	Uncertain	1.0
Eigen	Pathogenic	0.68
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Pathogenic	0.89	D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-2.0	N;N
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.018	D;D
Vest4		0.82
MutPred		0.88		Gain of relative solvent accessibility (P = 0.0999);Gain of relative solvent accessibility (P = 0.0999);
MVP		0.98
MPC		0.18
ClinPred		1.0	D
GERP RS		5.9
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: rs1060502443; hg19: chr13-32968853; COSMIC: COSV66452390; COSMIC: COSV66452390;