rs79456940

chr13-32340680-G-Achr13-32340680-G-Cchr13-32340680-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_000059.4(BRCA2):c.6325G>A(p.Val2109Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00014 in 1,608,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V2109F) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:17
• Conservation: PhyloP100: -0.217

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008333892).
• BP6: Variant 13-32340680-G-A is Benign according to our data. Variant chr13-32340680-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 41560.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=12, Benign=2, Uncertain_significance=2}. Variant chr13-32340680-G-A is described in Lovd as [Likely_benign]. Variant chr13-32340680-G-A is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.6325G>A	p.Val2109Ile	missense_variant	11/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.6325G>A	p.Val2109Ile	missense_variant	11/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152184 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00365

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000233 AC: 57 AN: 245084 Hom.: 0 AF XY: 0.000196 AC XY: 26 AN XY: 132644

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00315

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000142 AC: 207 AN: 1456484 Hom.: 0 Cov.: 44 AF XY: 0.000148 AC XY: 107 AN XY: 724394

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00510

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000832

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152302 Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74486

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00366

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000231 Hom.: 1

Bravo AF: 0.000113

ExAC AF: 0.000272 AC: 33

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:17

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Jan 18, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 19, 2019	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Oct 28, 2008	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -

not provided Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 01, 2016	Variant summary: The BRCA2 c.6325G>A (p.Val2109Ile) variant involves the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 38/122036 control chromosomes, predominantly observed in the East Asian subpopulation at a frequency of 0.0038354 (33/8604). This frequency is about 5 times the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503), suggesting this is likely a benign polymorphism found primarily in the populations of East Asian origin. The variant has been reported in numerous affected individuals in the literature, mostly of Asian origin, without strong evidence for causality. BIC reports the variant in 2 individuals who also carry pathogenic variants (BRCA1 c.4163_4164insA; BRCA2 c.9076C>T), also supportive of a benign outcome. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign/benign, although some classify it as a VUS. Taken together, this variant is classified likley benign. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 29, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 02, 2020	This variant is associated with the following publications: (PMID: 11595708, 19491284, 26709275, 27907908, 31131967, 30415210, 15117986, 14647438, 19016756, 27376475, 27124784, 22995991, 18779604, 15168169, 27658390, 28222693, 27997549, 27701467, 29215753, 28111427, 14973102, 28392550, 30725392, 29642553, 31825140, 22703879) -
Uncertain significance, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -

Hereditary cancer-predisposing syndrome Benign:4

Likely benign, criteria provided, single submitter	curation	University of Washington Department of Laboratory Medicine, University of Washington	Mar 23, 2023	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 03, 2015	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	May 01, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 04, 2018	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. -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 04, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Breast neoplasm Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University

Nov 01, 2015

- -

Cancer of the pancreas Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

3DMed Clinical Laboratory Inc

May 21, 2018

- -

BRCA2-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 05, 2023

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). -

Fanconi anemia complementation group D1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 19, 2019

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Malignant tumor of breast Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BRCA2 p.Val2109Ile variant was identified in 7 of 1460 proband chromosomes from Asian individuals with breast or ovarian cancer, and was absent in 520 control chromosomes from healthy individuals (Choi 2004, Haffty 2009, Hu 2004, Kawahara 2004, Sekine 2001, Sugano 2008). The variant was also identified in HGMD, UMD (1X as an unclassified variant), and the BIC database (8X with unknown clinical importance). The variant is listed in dbSNP (ID: rs79456940) “With unknown allele”, with a minor allele frequency of 0.0005 from the 1000 Genomes project, though this frequency is based on only one occurrence of the variant in the tested cohort. The p.Val2109 residue is not conserved in mammals and lower organisms, and the variant amino acid isoleucine (Ile) is present in dog, increasing the likelihood that this variant does not have clinical significance. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) do not suggest a high likelihood of impact to the protein, and Myriad classifies this as a polymorphism (personal communication). In addition, this variant was identified by our laboratory in one individual with a co-occurring pathogenic variant, further increasing the likelihood that this variant may not have clinical importance. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. -

Familial cancer of breast Benign:1

Likely benign, no assertion criteria provided

literature only

Center for Precision Medicine, Meizhou People's Hospital

-

- -

Hereditary breast ovarian cancer syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	0.094
Dann	Benign	0.52
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0046	N
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.0083	T;T
MetaSVM	Benign	-0.89	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.13	N;N
REVEL	Benign	0.092
Sift	Benign	0.55	T;T
Sift4G	Benign	0.40	T;T
Vest4		0.11
MVP		0.62
MPC		0.020
ClinPred		0.0095	T
GERP RS		-7.6
gMVP		0.13

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: rs79456940; hg19: chr13-32914817; COSMIC: COSV66465443;