rs370252983

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_000059.4(BRCA2):c.5411T>C(p.Val1804Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,613,802 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

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

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:5O:1

Conservation

PhyloP100: -0.388

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 Likely_benign. Variant got -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.13643035).

BP6

Variant 13-32339766-T-C is Benign according to our data. Variant chr13-32339766-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 133736.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=8, not_provided=1}. Variant chr13-32339766-T-C is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4 link	c.5411T>C	p.Val1804Ala	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.5411T>C	p.Val1804Ala	missense_variant	Exon 11 of 27	5	NM_000059.4	ENSP00000369497.3	P51587
BRCA2	ENST00000530893.7 link	c.5042T>C	p.Val1681Ala	missense_variant	Exon 11 of 27	1		ENSP00000499438.2	A0A590UJI7
BRCA2	ENST00000614259.2 link	n.5411T>C		non_coding_transcript_exon_variant	Exon 10 of 26	2		ENSP00000506251.1	A0A7P0TAP7

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152162

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:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000319

AC:

AN:

251140

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135776

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000229

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000178

AC:

AN:

1461640

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

727110

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000209

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74330

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:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000165

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:5Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:2

Nov 16, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces valine with alanine at codon 1804 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 individuals affected with breast cancer and a healthy control (PMID: 14722926, 24728327, 25682074), one of these individuals also carried a known pathogenic variant in the BRCA2 gene that could explain the observed phenotype (PMID: 14722926). In a large breast cancer case-control study conducted by the BRIDGES consortium, this variant was reported in 1/60466 cases and 3/53461 controls (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_002145). This variant has been identified in 8/251140 chromosomes 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. -

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). -

Jul 29, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Aug 17, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:1Benign:3

Neuberg Centre For Genomic Medicine, NCGM

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant c.5411T>C(p.Val1804Ala) has been previously reported in individuals affected with breast and/or ovarian cancer (Saxena et. al., 2006; Valarmathi et. al., 2004). The p.Val1804Ala variant is novel (not in any individuals) in 1000 Genomes and has allele frequency of 0.003% in gnomAD database. This variant has been reported to the ClinVar database as Variant of Uncertain Significance/Likely benign. The amino acid Val at position 1804 is changed to a Ala changing protein sequence and it might alter its composition and physico-chemical properties. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Therefore, it has been classified as a Variant of Uncertain Significance (VUS). The classification is likely to change as more data becomes available for this variant. -

Nov 12, 2024

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. -

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 28, 2017

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Uncertain:2

Oct 04, 2021

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 5639T>C; Observed in individuals with a personal or family history of breast and/or ovarian cancer (Saxena 2006, Valarmathi 2004); This variant is associated with the following publications: (PMID: 17018160, 31131967, 24728327, 14722926) -

Mar 15, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.5411T>C (p.Val1804Ala) variant has been reported in the published literature in individuals with breast cancer (PMID: 33471991 (2021), 25682074 (2015), 14722926 (2004), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA2)). This variant has also been identified in reportedly healthy individuals (PMID: 33471991 (2021), 24728327 (2014), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA2)). In an individual with early onset breast cancer, the variant co-occurred with a pathogenic BRCA2 frameshift variant, which suggests the BRCA2 c.5411T>C variant is not the primary cause of disease (PMID: 14722926 (2004)). The frequency of this variant in the general population, 0.00023 (7/30600 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

not specified

Uncertain:1Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Sep 11, 2020

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.5411T>C (p.Val1804Ala) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251240 control chromosomes (gnomAD and publication). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5411T>C has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer Syndrome (Wong-Brown_2015, Valarmathi_2004). These reports however, do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. Co-occurrence with another pathogenic variant has been reported (BRCA2 c.5227dupT), providing supporting evidence for a benign role (Valarmathi_2004). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=4) or likely benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance. -

BRCA2-related cancer predisposition

Uncertain:1

May 30, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary breast ovarian cancer syndrome

Uncertain:1

Oct 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 1804 of the BRCA2 protein (p.Val1804Ala). This variant is present in population databases (rs370252983, gnomAD 0.03%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 14722926, 17018160, 25682074). ClinVar contains an entry for this variant (Variation ID: 133736). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.35

CADD

Benign

4.5

DANN

Benign

0.86

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.033

M_CAP

Benign

0.022

MetaRNN

Benign

0.14

T;T

MetaSVM

Benign

-0.92

PrimateAI

Benign

0.27

PROVEAN

Uncertain

-3.2

D;D

REVEL

Benign

0.17

Sift

Uncertain

0.014

D;D

Sift4G

Uncertain

0.029

D;D

Vest4

0.32

MutPred

0.36

Gain of disorder (P = 0.0683);Gain of disorder (P = 0.0683);

MVP

0.79

MPC

0.032

ClinPred

0.081

GERP RS

-0.19

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

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