rs397507365

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1BP6

The NM_000059.4(BRCA2):c.6196G>A(p.Val2066Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,612,716 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10B:3

Conservation

PhyloP100: 7.78

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM1

In a repeat BRCA2 8 (size 34) in uniprot entity BRCA2_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_000059.4

BP6

Variant 13-32340551-G-A is Benign according to our data. Variant chr13-32340551-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 38024.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=9}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4 link	c.6196G>A	p.Val2066Ile	missense_variant	Exon 11 of 27	ENST00000380152.8	NP_000050.3	P51587

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
BRCA2	ENST00000380152.8 link	c.6196G>A	p.Val2066Ile	missense_variant	Exon 11 of 27	5	NM_000059.4	ENSP00000369497.3	P51587
BRCA2	ENST00000530893.7 link	c.5827G>A	p.Val1943Ile	missense_variant	Exon 11 of 27	1		ENSP00000499438.2	A0A590UJI7
BRCA2	ENST00000614259.2 link	n.6196G>A		non_coding_transcript_exon_variant	Exon 10 of 26	2		ENSP00000506251.1	A0A7P0TAP7

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460522

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726460

show subpopulations

Gnomad4 AFR exome

AF:

0.0000599

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.000121

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:4

Jan 09, 2012

Sharing Clinical Reports Project (SCRP)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 07, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces valine with isoleucine at codon 2066 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with prostate cancer (PMID: 35666082). A multifactorial analysis using co-occurrence with another pathogenic variant and family history likelihood ratios has determined that this variant is unlikely to be disease-causing (PMID: 31131967). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Apr 21, 2016

Michigan Medical Genetics Laboratories, University of Michigan

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 05, 2017

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Uncertain:3Benign:1

Jan 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.V2066I variant (also known as c.6196G>A), located in coding exon 10 of the BRCA2 gene, results from a G to A substitution at nucleotide position 6196. The valine at codon 2066 is replaced by isoleucine, an amino acid with highly similar properties. This alteration was identified amongst a cohort of 427 patients undergoing genetic testing due to a diagnosis of prostate cancer (Giri VN et al. JCO Precis Oncol, 2022 May;6:e2200234). This alteration was classified as likely benign in a multifactorial model of variant interpretation that incorporates co-segregation, family history, co-occurrence and tumor pathology and case-control data (Parsons MT et al. Hum Mutat, 2019 09;40:1557-1578). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Mar 23, 2023

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -

May 20, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Feb 14, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided

Uncertain:1Benign:1

Nov 05, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26155992, 31131967) -

Dec 05, 2017

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Uncertain:1

Dec 23, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRCA2 c.6196G>A (p.Val2066Ile) results in a conservative amino acid change located in the BRCA2 repeat region (IPR002093) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.3e-05 in 152194 control chromosomes, exclusively found within the African/African American subpopulation (i.e. 5/41448 alleles; frequency: 0.00012) in the gnomAD v3.1 database, genomes dataset. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6196G>A has been reported in the literature in a prostate cancer patient, however without strong evidence for causality (e.g., Giri_2022), as well as detected in a tumor sample from a patient with cervical squamous cell carcinoma, but without corresponding testing of germline DNA and without causative evidence related to the disease (e.g., Muller_2015). These reports therefore do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. A co-occurrence with another pathogenic variant has been reported (BRCA2 c.7558C>T (p.Arg2520X), in an internal LCA sample), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A recent multifactorial likelihood analysis predicted this variant to be likely benign (Parsons_2019). The following publications have been ascertained in the context of this evaluation (PMID: 31294896, 35666082, 26155992, 31112341, 31131967). ClinVar contains an entry for this variant (Variation ID: 38024). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Medulloblastoma;C0346153:Familial cancer of breast;C1838457:Fanconi anemia complementation group D1;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2;C2751641:Glioma susceptibility 3;C2931456:Familial prostate cancer;C3150546:Pancreatic cancer, susceptibility to, 2;CN033288:Wilms tumor 1

Uncertain:1

Feb 15, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome

Benign:1

Nov 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.070

CADD

Uncertain

DANN

Uncertain

1.0

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Pathogenic

0.99

M_CAP

Benign

0.063

MetaRNN

Uncertain

0.44

T;T

MetaSVM

Uncertain

0.014

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.83

N;N

REVEL

Uncertain

0.33

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Vest4

0.47

MutPred

0.34

Gain of catalytic residue at V2066 (P = 0.0319);Gain of catalytic residue at V2066 (P = 0.0319);

MVP

0.86

MPC

0.16

ClinPred

0.94

GERP RS

5.8

gMVP

0.22

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

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