rs80359418

chr13-32316462-TG-T

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_000059.4(BRCA2):c.3del(p.Met1?) variant causes a frameshift, start lost change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: BRCA2 NM_000059.4 frameshift, start_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 5.44

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 20 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 3888 pathogenic variants in the truncated region.
• PS1: Another start lost variant in NM_000059.4 (BRCA2) was described as [Pathogenic] in ClinVar as 51579
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-32316462-TG-T is Pathogenic according to our data. Variant chr13-32316462-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 37872.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-32316462-TG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.3del	p.Met1?	frameshift_variant, start_lost	2/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.3del	p.Met1?	frameshift_variant, start_lost	2/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Dec 23, 2003	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Jan 26, 2012	- -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

MGZ Medical Genetics Center

Apr 06, 2022

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 16, 2017

The c.3delG pathogenic mutation, located in coding exon 1 of the BRCA2 gene, results from a deletion of one nucleotide (G) at nucleotide position 3. This alters the methionine residue at the initiation codon (p.M1?). While this specific alteration has not been reported in the literature to date, several other missense mutations (c.2T>G, c.3G>A, and c.2T>C) that alter the methionine residue at the initiation codon in BRCA2 (p.M1?) have been reported in breast and/or ovarian cancer families (Santos C et al. J Mol Diagn 2014 May;16(3):324-34; Thomassen M, Breast Cancer Res. Treat. 2012 Apr; 132(3):1009-23; Jakubowska, A et al. Eur J Hum Genet. 2003 Dec;11(12):955-8; Ambry internal data). Since sequence variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame, the c.3delG alteration is interpreted as a disease-causing mutation. -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 03, 2023

For these reasons, this variant has been classified as Pathogenic. This sequence change affects the initiator methionine of the BRCA2 mRNA. The next in-frame methionine is located at codon 124. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with colorectal cancer (PMID: 14647210, 18182601, 21769658, 24156927, 25330149, 29478780; Invitae). ClinVar contains an entry for this variant (Variation ID: 37872). While this variant is expected to result in an absent protein product, possible rescue of translational initiation by the downstream methionine would lead to the disruption of the N-terminal part of the BRCA2 protein that interacts with PALB2 (residues 18-40), which is critical for BRCA2-mediated homologous recombinational DNA repair (PMID: 16793542, 22678057, 19369211). This variant disrupts the p.Met1 amino acid residue in BRCA2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14647210, 18182601, 21769658, 24156927, 25330149; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. -

Computational scores

Source: dbNSFP v4.3

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: rs80359418; hg19: chr13-32890599;