rs11571641

Positions:

• chr13-32332873-A-C
• chr13-32332873-A-G
• chr13-32332873-A-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_000059.4(BRCA2):​c.1395A>C​(p.Val465=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000621 in 1,611,462 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00066 (0 hom.)
• Consequence: BRCA2 NM_000059.4 synonymous
• Clinical Significance: Likely benign reviewed by expert panel U:1 B:26
• Conservation: PhyloP100: 0.143

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 13-32332873-A-C is Benign according to our data. Variant chr13-32332873-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 51116.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32332873-A-C is described in Lovd as [Likely_benign]. Variant chr13-32332873-A-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.143 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.1395A>C	p.Val465=	synonymous_variant	10/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.1395A>C	p.Val465=	synonymous_variant	10/27	5	NM_000059.4	ENSP00000369497	A2

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152226 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

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: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000250 AC: 62 AN: 248262 Hom.: 0 AF XY: 0.000268 AC XY: 36 AN XY: 134266

Gnomad AFR exome AF: 0.0000620

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000927

Gnomad NFE exome AF: 0.000514

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000660 AC: 963 AN: 1459236 Hom.: 0 Cov.: 35 AF XY: 0.000628 AC XY: 456 AN XY: 725734

Gnomad4 AFR exome AF: 0.000180

Gnomad4 AMR exome AF: 0.0000227

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.000837

Gnomad4 OTH exome AF: 0.000315

GnomAD4 genome AF: 0.000250 AC: 38 AN: 152226 Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74378

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000485

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000354 Hom.: 0

Bravo AF: 0.000238

EpiCase AF: 0.000600

EpiControl AF: 0.000356

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:26

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1 Benign:8

Likely benign, criteria provided, single submitter	literature only	Counsyl	Apr 17, 2014	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Jun 29, 2017	Synonymous substitution variant, with low bioinformatic likelihood to result in a splicing aberration (Splicing prior probability 0.02; http://priors.hci.utah.edu/PRIORS/). -
Likely benign, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Michigan Medical Genetics Laboratories, University of Michigan	Apr 21, 2016	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Dec 30, 1999	- -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 31, 2017	- -

not specified Benign:6

Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	Apr 18, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 20, 2022	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 11, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The BRCA2 p.Val465Val variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict the abolishment of an existing splice site or the creation of a new splice site, and a splicing minigene assay found the variant did not have an effect on splicing (Théry 2011). The variant was identified in the literature in 2 of 8048 proband chromosomes from individuals or families with breast or ovarian cancer; however control chromosomes were not evaluated in this study thus the prevalence of the variant in the general population could not be determined (van der Hout 2006). Another variant with the same synonymous amino acid change but a different nucleotide change (c.1395A>T) was identified in one individual with breast cancer in a study by Evans (2008); however, control chromosomes were not included in this study. The p.Val465Val variant was identified in the NIH Polymorphism Discovery Resource (NIHPDR) PDR90 cohort in 1 of 180 chromosomes (frequency: 0.006), and in the Exome Variant Server Exome Sequencing Project in 4 of 13006 European American alleles (frequency 0.0003), increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. The variant was also identified in dbSNP (ID: rs11571641) “With uncertain allele”, HGMD, LOVD, the ClinVar database (classified as benign by Invitae and GeneDx), the BIC database (1X with unknown clinical importance), and UMD (25X as a neutral variant). In UMD the variant was identified with three different co-occurring pathogenic BRCA2 variants and one pathogenic BRCA1 variant, increasing the likelihood that the p.Val465Val variant does not have clinical significance. Furthermore, Myriad classifies this as a polymorphism (personal communication). In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 21, 2014	- -

not provided Benign:4

Likely 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	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	BRCA2: BP4, BP7 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 14, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 13, 2014	This alteration is classified as likely 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	curation	Sema4, Sema4	Apr 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 22, 2015	- -

Hereditary breast ovarian cancer syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Feb 14, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Medulloblastoma;C0346153:Familial cancer of breast;C0376358:Malignant tumor of prostate;C1838457:Fanconi anemia complementation group D1;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2;C2751641:Glioma susceptibility 3;C3150546:Pancreatic cancer, susceptibility to, 2;CN033288:Wilms tumor 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 17, 2022

- -

Breast and/or ovarian cancer Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Dec 01, 2022

- -

BRCA2-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 05, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.53
DANN	Benign	0.49

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: rs11571641; hg19: chr13-32907010;