Variant rs80358650 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong

The NM_000059.4(BRCA2):c.3G>A(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000657 in 152,158 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Consequence

BRCA2
NM_000059.4 start_lost

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:15O:1

Conservation

PhyloP100: 5.44

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]

BRCA2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 20 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PS1

Another start lost variant in NM_000059.4 (BRCA2) was described as [Pathogenic] in Lovd

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 13-32316463-G-A is Pathogenic according to our data. Variant chr13-32316463-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 51579.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32316463-G-A is described in Lovd as [Pathogenic]. Variant chr13-32316463-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4 linkuse as main transcript	c.3G>A	p.Met1?	start_lost	2/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8 linkuse as main transcript	c.3G>A	p.Met1?	start_lost	2/27	5	NM_000059.4	ENSP00000369497	A2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2

Pathogenic:7Other:1

not provided, no classification provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 14, 2018	- -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 04, 2016	- -
Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Jun 18, 2019	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 0.999736 -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Medical Genetics, Oslo University Hospital	Jan 20, 2017	- -
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	Sharing Clinical Reports Project (SCRP)	Jul 17, 2009	- -

Hereditary cancer-predisposing syndrome

Pathogenic:3

Pathogenic, criteria provided, single submitter	research	Hauer Lab, Department Of Pediatric Oncology, Technical University Munich	-	ACMG/AMP, PVS1, PM2, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 23, 2020	This variant results in the loss of the translation start codon of the BRCA2 protein. 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 been reported in individuals affected with breast cancer (PMID: 20104584, 21769658, 28807866) and in a hereditary breast/ovarian cancer family (PMID: 21203900). This variant has also been analyzed by multifactorial analysis and classified as pathogenic based in part on segregation and tumor pathology likelihood ratios of 67.6 and 2.7, respectively (PMID: 31131967). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 02, 2023	The p.M1? pathogenic mutation (also known as c.3G>A) is located in coding exon 1 of the BRCA2 gene and results from a G to A substitution at nucleotide position 3. This alters the methionine residue at the initiation codon (ATG). This mutation has been identified in one kindred with familial breast cancer in which three members were affected; two were diagnosed at age 45 and one at age 37 (Thomassen M et al. Breast Cancer Res. Treat. 2012 Apr;132(3):1009-23). In addition to the clinical data presented in the literature, sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Hereditary breast ovarian cancer syndrome

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 15, 2021	The p.Met1Ile variant in BRCA2 has been reported in at least 10 individuals with BRCA2-associated cancers (Borg 2010 PMID:20104584, Thomassen 2012 PMID:21769658, Breast Cancer Information Core (BIC) database: https://research.nhgri.nih.gov/bic/) and in >10 individuals with a family history of breast and ovarian cancer (HBOC) that had undergone clinical genetic testing (Konecny 2011 PMID: 21203900, Meisel 2017 PMID:28324225; Heramb 2018 PMID:29339979, Rebbeck 2018 PMID: 29446198). It has also been identified in 0.001% (1/68028) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1). This variant affects the translation initiation start codon (ATG) and is therefore predicted to disrupt translation through a variety of outcomes (no protein synthesis or the activation of an upstream translation initiation codon), though the precise effect cannot be predicted. Of note, a possible alternate initiation codon location exists downstream at codon 124, which would result in a protein that is missing 4% of the coding region. In vitro functional studies support an impact on protein function (Mesman 2018 PMID:29988080). Additionally, this variant was classified as Pathogenic on Jun 18, 2019 by the ClinGen-approved ENIGMA expert panel (Variation ID 51579). Other variants affecting this translation initiation codon have been identified in individuals with HBOC in ClinVar. In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HBOC. ACMG/AMP criteria applied: PS4_Strong, PM2_Supporting, PVS1_Moderate, PS3_Supporting, PM5_Supporting. -
Pathogenic, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Jan 31, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	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 breast and/or ovarian cancer (PMID: 29478780). ClinVar contains an entry for this variant (Variation ID: 51579). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 21769658). 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. For these reasons, this variant has been classified as Pathogenic. -

Breast and/or ovarian cancer

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

CZECANCA consortium

Jun 11, 2019

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Nov 03, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.22

CADD

Benign

DANN

Uncertain

1.0

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.90

M_CAP

Pathogenic

0.92

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Benign

-1.1

MutationTaster

Benign

1.0

D;D

PROVEAN

Benign

-0.96

N;N

REVEL

Uncertain

0.40

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Vest4

0.92

MutPred

0.99

Gain of catalytic residue at M1 (P = 0.0193);Gain of catalytic residue at M1 (P = 0.0193);

MVP

0.94

ClinPred

1.0

GERP RS

5.3

gMVP

0.51

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over