rs80359198

Positions:

• chr13-32394717-C-A
• chr13-32394717-C-G
• chr13-32394717-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PS1 PM2 PP3_Strong PP5_Very_Strong

The NM_000059.4(BRCA2):​c.9285C>A​(p.Asp3095Glu) variant causes a missense change involving the alteration of a non-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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin Lovd. Synonymous variant affecting the same amino acid position (i.e. D3095D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 1.46

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 18 ACMG points.

• PS1: Transcript NM_000059.4 (BRCA2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.965
• PP5: Variant 13-32394717-C-A is Pathogenic according to our data. Variant chr13-32394717-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 252859.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.9285C>A	p.Asp3095Glu	missense_variant	25/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.9285C>A	p.Asp3095Glu	missense_variant	25/27	5	NM_000059.4	ENSP00000369497	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jan 17, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Jul 17, 2013	- -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

May 19, 2022

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Feb 07, 2020

This missense variant replaces aspartic acid with glutamic acid at codon 3095 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). While this particular variant has not been reported in the literature, a different variant (c.9285C>G) resulting in the same protein effect has been shown to disrupt homology-directed DNA repair activity (PMID: 18451181, 23108138, 29884841) and to fail to complement cell lethality phenotype induced by loss of BRCA2 in mouse embryonic stem cell-based assays (PMID: 24323938, 29988080). c.9285C>G has also been reported in many individuals affected with breast cancer (PMID: 16875939, 18951446, 28477318, 30728895) and prostate cancer (PMID: 29368341, 29439820, 29983880, 30293905). In addition, several multifactorial likelihood models using health history, in silico, and experimental data have suggested p.Asp3095Glu have a high probability of being pathogenic (PMID: 17924331, 19043619, 21990134, 25085752, 29394989). These data indicate that replacing aspartic acid with glutamic acid at this codon position is disease-causing. Based on the available evidence, this variant is classified as Pathogenic. -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 21, 2023

This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 3095 of the BRCA2 protein (p.Asp3095Glu). This variant is not present in population databases (gnomAD no frequency). A different variant (c.9285C>G) giving rise to the same protein effect has been determined to be pathogenic (PMID: 17924331, 18451181, 18951446, 21990134, 22678057, 23108138). This suggests that this variant is also likely to be causative of disease. ClinVar contains an entry for this variant (Variation ID: 252859). 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: 32444794). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Benign	16
DANN	Uncertain	0.99
Eigen	Benign	0.19
Eigen_PC	Benign	0.085
FATHMM_MKL	Uncertain	0.77	D
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Uncertain	0.66	D
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.2	N;N
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.023	D;D
Vest4		0.68
MutPred		0.96		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		0.96
MPC		0.16
ClinPred		0.99	D
GERP RS		3.5
gMVP		0.71

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: rs80359198; hg19: chr13-32968854; COSMIC: COSV66461589; COSMIC: COSV66461589;