rs59004709

chr13-32379467-G-Achr13-32379467-G-Cchr13-32379467-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_000059.4(BRCA2):c.8905G>A(p.Val2969Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000177 in 1,613,290 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V2969A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Benign reviewed by expert panel U:6 B:17
• Conservation: PhyloP100: 2.76

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05979395).
• BP6: Variant 13-32379467-G-A is Benign according to our data. Variant chr13-32379467-G-A is described in ClinVar as [Benign]. Clinvar id is 52697.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32379467-G-A is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.8905G>A	p.Val2969Met	missense_variant	22/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.8905G>A	p.Val2969Met	missense_variant	22/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152176 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

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: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000301 AC: 75 AN: 249494 Hom.: 0 AF XY: 0.000274 AC XY: 37 AN XY: 134896

Gnomad AFR exome AF: 0.000310

Gnomad AMR exome AF: 0.000117

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000329

Gnomad FIN exome AF: 0.000462

Gnomad NFE exome AF: 0.000480

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000177 AC: 259 AN: 1460996 Hom.: 0 Cov.: 31 AF XY: 0.000171 AC XY: 124 AN XY: 726752

Gnomad4 AFR exome AF: 0.000389

Gnomad4 AMR exome AF: 0.000135

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000375

Gnomad4 NFE exome AF: 0.000184

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152294 Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74468

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000289 Hom.: 0

Bravo AF: 0.000227

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000404 AC: 49

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000296

ClinVar

Significance: Benign

Submissions summary: Uncertain:6 Benign:17

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:3 Benign:4

Benign, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Aug 10, 2015	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000011 -
Likely benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 11, 2024	- -
Benign, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -
Uncertain significance, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Nov 06, 2006	- -
Likely benign, criteria provided, single submitter	literature only	Counsyl	Mar 20, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 25, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 09, 2020	This variant is associated with the following publications: (PMID: 21232165, 18559594, 21965345, 18375895, 20104584, 25948282, 26780556, 24323938, 28324225, 28678401, 17924331, 21990134, 29884841) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	BRCA2: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 02, 2020	- -

Hereditary cancer-predisposing syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 19, 2014	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 23, 2015	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jul 12, 2021	- -

Breast and/or ovarian cancer Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Jun 25, 2020

- -

Fanconi anemia complementation group D1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Malignant tumor of breast Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BRCA2 p.Val2969Met variant was identified in 6 of 9554 proband chromosomes (frequency: 0.001) from individuals or families with hereditary breast and ovarian cancer and was not identified in 80 control chromosomes from healthy individuals (Akbari 2011, Borg 2010, Soegaard 2008, Stegel 2011, Kluska 2015). The variant was also identified by our laboratory in 1 individual with hereditary breast and ovarian cancer. The variant was also identified in dbSNP (ID: rs59004709) as “other”, Clinvitae database (as benign), Fanconi Anemia Mutation Database -LOVD (3x, as predicted neutral 2x and predicted deleterious 1x), LOVD-IARC database (as not pathogenic), ARUP Laboratories BRCA Mutations Database (as not pathogenic), the ClinVar database (as benign, reviewed by an expert panel), GeneInsight COGR database (as “benign”, “likely benign”, and “unknown significance”, by clinical laboratories), the BIC database (24x with unknown clinical importance), and UMD (23x with a “likely neutral” classification). This variant was identified in the 1000 Genomes Project in 3 of 5000 chromosomes (frequency: 0.0006), NHLBI GO Exome Sequencing Project in 2 of 8600 European American alleles and 1 of 4406 African American alleles, and in the Exome Aggregation Consortium database (March 14, 2016) in 49 of 120422 chromosomes (freq. 0.0004) in the following populations: European (Non-Finnish) in 41 of 66196 chromosomes (freq. 0.0006), European (Finnish) in 4 of 6614 chromosomes (freq. 0.0006), and African in 4 of 10180 chromosomes (freq. 0.0004), but was not seen in East Asian, Latino, South Asian and other populations, increasing the likelihood this could be a low frequency benign variant. There is conflicting information in the literature. Two in-silico functional studies suggest this variant is predicted neutral (Easton 2007, Lindor 2012), while two others suggest the variant is likely deleterious (Karchin 2008, Kluska 2015). The p.Val2969 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Hereditary breast ovarian cancer syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.18
Cadd	Benign	23
Dann	Uncertain	1.0
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.84	D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.060	T;T
MetaSVM	Benign	-0.74	T
MutationTaster	Benign	0.99	D;D
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.83	N;N
REVEL	Uncertain	0.30
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0030	D;D
Vest4		0.29
MVP		0.83
MPC		0.12
ClinPred		0.061	T
GERP RS		0.67
gMVP		0.46

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: rs59004709; hg19: chr13-32953604; COSMIC: COSV66451207; COSMIC: COSV66451207;