rs431825354

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_000059.4(BRCA2):c.7628A>G(p.Tyr2543Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,612,100 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:19B:1

Conservation

PhyloP100: 0.730

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:

BRCA2 (HGNC:):

BRCA2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4 linkuse as main transcript	c.7628A>G	p.Tyr2543Cys	missense_variant	16/27	ENST00000380152.8	NP_000050.3	P51587

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
BRCA2	ENST00000380152.8 linkuse as main transcript	c.7628A>G	p.Tyr2543Cys	missense_variant	16/27	5	NM_000059.4	ENSP00000369497.3	P51587
BRCA2	ENST00000530893.7 linkuse as main transcript	c.7259A>G	p.Tyr2420Cys	missense_variant	16/27	1		ENSP00000499438.2	A0A590UJI7
BRCA2	ENST00000614259.2 linkuse as main transcript	n.7628A>G		non_coding_transcript_exon_variant	15/26	2		ENSP00000506251.1	A0A7P0TAP7

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152120

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000319

AC:

AN:

250888

Hom.:

AF XY:

0.0000369

AC XY:

AN XY:

135660

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:

0.000196

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000199

AC:

AN:

1459980

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

726442

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:

0.000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152120

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74322

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:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:19Benign:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:5Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	May 01, 2012	- -
Uncertain significance, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jun 06, 2023	a point mutation in the BRCA2 gene (c.7628A>G (p.Tyr2543Cys)) which results in the substitution of cysteine for tyrosine at amino acid position 2543. This mutation is considered as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Feb 04, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Sep 06, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 08, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Department of Medical and Surgical Sciences, University of Bologna	Sep 01, 2023	BS1(Supporting)+BP4(Supporting) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042) -

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 25, 2024	The BRCA2 c.7628A>G (p.Tyr2543Cys) variant has been reported in individuals affected with breast cancer (PMIDs: 33471991 (2021), 30199306 (2018), see also LOVD (http://databases.lovd.nl/shared)) and ovarian cancer (PMID: 35864222 (2022). Published functional studies have reported inconclusive findings on the effect of this variant on BRCA2 protein function (PMIDs: 30696104 (2019), 31721781 (2019)). The frequency of this variant in the general population, 0.0002 (6/30596 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 31, 2023	Observed in individuals with a personal history of breast or ovarian cancer (PMID: 30199306, 34271787, 33471991); Published functional studies are inconclusive: proficient binding to DSS1, increased relative mRNA expression and radial chromosome formation similar to wildtype, but reduced relative viability of cells following treatment with mitomycin C (PMID: 30696104, 31721781); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 7856A>G; This variant is associated with the following publications: (PMID: 30696104, 31721781, 34271787, 33773534, 30199306, 33471991, 12228710, 32720237, Al-AliA2023[preprint]) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 19, 2023	- -

Hereditary cancer-predisposing syndrome

Uncertain:3

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Feb 17, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 13, 2024	The p.Y2543C variant (also known as c.7628A>G), located in coding exon 15 of the BRCA2 gene, results from an A to G substitution at nucleotide position 7628. The tyrosine at codon 2543 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been detected in multiple breast cancer cohorts (Abulkhair O et al. J Glob Oncol, 2018 08;4:1-9; Chapman-Davis E et al. J Gen Intern Med, 2021 01;36:35-42; Tariq H et al. Asian Pac J Cancer Prev, 2021 Mar;22:719-724; Yao L et al. J Hum Genet, 2022 Nov;67:639-642). This alteration also demonstrated no effect on BRCA2/DSS1 binding in one functional study (Caleca L et al. Cancers (Basel), 2019 Jan;11). This amino acid position is not well 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 variant remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 20, 2023	This missense variant replaces tyrosine with cysteine at codon 2543 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study reported that this variant impacts BRCA2 function in the rescue of BRCA2-deficient cells in cell viability after mitomycin C treatment and G2/M cell cycle arrest (PMID: 31721781). This variant has been reported in at least five individuals affected with breast cancer (PMID: 30199306, 33471991; Leiden Open Variation Database DB-ID BRCA2_006703, 33773534) and an individual affected with childhood T-cell acute lymphoblastic leukemia (PMID: 31721781). This variant has been identified in 8/250888 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. -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 22, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 06, 2023	Variant summary: BRCA2 c.7628A>G (p.Tyr2543Cys) results in a non-conservative amino acid change located in the Breast cancer type 2 susceptibility protein, helical domain (IPR015252) of 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 3.2e-05 in 250888 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7628A>G has been reported in the literature as a VUS in individuals affected with breast cancer (example, Abulkhair_2018, Tariq_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. One publication reports experimental evidence evaluating an impact on protein function with no impact on BRCA2/DSS1 binding, however the data as presented does not allow convincing conclusions about the variant effect (Caleca_2019). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

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

Sep 16, 2022

- -

BRCA2-related cancer predisposition

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

May 30, 2024

This missense variant replaces tyrosine with cysteine at codon 2543 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study reported that this variant impacts BRCA2 function in the rescue of BRCA2-deficient cells in cell viability after mitomycin C treatment and G2/M cell cycle arrest (PMID: 31721781). This variant has been reported in at least five individuals affected with breast cancer (PMID: 30199306, 33471991; Leiden Open Variation Database DB-ID BRCA2_006703, 33773534) and an individual affected with childhood T-cell acute lymphoblastic leukemia (PMID: 31721781). This variant has been identified in 8/250888 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. -

BRCA2-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 31, 2023

The BRCA2 c.7628A>G variant is predicted to result in the amino acid substitution p.Tyr2543Cys. This variant has been reported in individuals with breast cancer (Abulkhair et al. 2018. PubMed ID: 30199306; Tariq et al. 2021. PubMed ID: 33773534). This variant is reported in 0.020% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-32931889-A-G) and is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/96855/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Familial cancer of breast

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 04, 2023

- -

Hereditary breast ovarian cancer syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 10, 2023

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 2543 of the BRCA2 protein (p.Tyr2543Cys). This variant is present in population databases (rs431825354, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer (PMID: 30199306, 33773534). ClinVar contains an entry for this variant (Variation ID: 96855). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on BRCA2 function (PMID: 30696104, 31721781). 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

0.082

BayesDel_addAF

Benign

-0.042

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

DANN

Uncertain

1.0

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.35

FATHMM_MKL

Uncertain

0.80

M_CAP

Benign

0.067

MetaRNN

Uncertain

0.60

D;D

MetaSVM

Benign

-0.67

PrimateAI

Benign

0.38

PROVEAN

Uncertain

-2.4

N;N

REVEL

Pathogenic

0.67

Sift

Benign

0.079

T;T

Sift4G

Benign

0.13

T;T

Vest4

0.58

MutPred

0.71

Loss of stability (P = 0.0584);Loss of stability (P = 0.0584);

MVP

0.90

MPC

0.17

ClinPred

0.14

GERP RS

-0.17

gMVP

0.41

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