chr13-32346895-C-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM5BP4_StrongBP6

The NM_000059.4(BRCA2):c.7006C>T(p.Arg2336Cys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000181 in 1,604,296 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/21 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. R2336H) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense, splice_region

Scores

Splicing: ADA: 0.0002450

Clinical Significance

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

Conservation

PhyloP100: 0.0390

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.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr13-32346896-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 38077.Status of the report is reviewed_by_expert_panel, 3 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.049040914).

BP6

Variant 13-32346895-C-T is Benign according to our data. Variant chr13-32346895-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 96845.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=8, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4 link	c.7006C>T	p.Arg2336Cys	missense_variant, splice_region_variant	Exon 13 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.7006C>T	p.Arg2336Cys	missense_variant, splice_region_variant	Exon 13 of 27	5	NM_000059.4	ENSP00000369497.3	P51587
BRCA2	ENST00000530893.7 link	c.6637C>T	p.Arg2213Cys	missense_variant, splice_region_variant	Exon 13 of 27	1		ENSP00000499438.2	A0A590UJI7
BRCA2	ENST00000614259.2 link	n.7006C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 12 of 26	2		ENSP00000506251.1	A0A7P0TAP7

Frequencies

GnomAD3 genomes

AF:

0.0000855

AC:

AN:

152018

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

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:

0.00000807

AC:

AN:

247890

Hom.:

AF XY:

0.0000149

AC XY:

AN XY:

134068

show subpopulations

Gnomad AFR exome

AF:

0.0000619

Gnomad AMR exome

AF:

0.0000294

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

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:

0.0000110

AC:

AN:

1452160

Hom.:

Cov.:

AF XY:

0.0000125

AC XY:

AN XY:

722552

show subpopulations

Gnomad4 AFR exome

AF:

0.0000601

Gnomad4 AMR exome

AF:

0.0000677

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000236

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000814

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152136

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.000289

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000453

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:3

Dec 13, 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 arginine with cysteine at codon 2336 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 a breast cancer case-control meta-analysis in 1/60463 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_005905) and in families suspected of being affected with hereditary breast and ovarian cancer (PMID: 22366370, 29161300). This variant has been identified in 4/279248 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. -

Oct 18, 2011

Sharing Clinical Reports Project (SCRP)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 03, 2014

Michigan Medical Genetics Laboratories, University of Michigan

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Uncertain:2Benign:1

Jun 20, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in individuals with a personal or family history of breast and/or ovarian cancer (Levanat et al., 2012; Alemar et al., 2017); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 7234C>T; This variant is associated with the following publications: (PMID: 31143303, 29541205, 29161300, 22366370, 32297440, 37129948, 32467295) -

Oct 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.7006C>T (p.Arg2336Cys) variant has been reported in the published literature in individuals affected with breast and/or ovarian cancer (PMID: 22366370 (2012), 29161300 (2017), 33471991 (2021), 38509102 (2024)). The variant has also been reported in an unaffected individual (PMID: 32467295 (2020)). Splicing studies have shown that this variant results in normal splicing patterns and unaltered transcripts (PMID: 31143303 (2019)). The frequency of this variant in the general population, 0.00012 (3/24854 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. -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BRCA2: BP4, BS1:Supporting -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Mar 09, 2018

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. -

Nov 08, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified

Uncertain:1

Oct 24, 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.7006C>T (p.Arg2336Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Wangensteen_2019). The variant allele was found at a frequency of 1.8e-05 in 1604526 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (1.8e-05 vs 0.00075), allowing no conclusion about variant significance. c.7006C>T has been reported in the literature in individuals with a personal and/or family history of Hereditary Breast and Ovarian Cancer and pancreatic ductal adenocarcinoma (Levanat_2012, Alemar_2017, Militello_2023, Bhai_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrence with another pathogenic variant has been reported at our laboratory, BRCA1 c.5324T>G(p.Met1775Arg), providing supporting evidence for a benign role. At least one publication reports experimental evidence that this variant has no impact on protein function (Sahu_2023). The following publications have been ascertained in the context of this evaluation (PMID: 29161300, 34326862, 18844490, 22366370, 37725113, 37713444, 31143303). ClinVar contains an entry for this variant (Variation ID: 96845). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Breast and/or ovarian cancer

Uncertain:1

Jan 21, 2021

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

BRCA2-related disorder

Uncertain:1

Mar 20, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRCA2 c.7006C>T variant is predicted to result in the amino acid substitution p.Arg2336Cys. This variant was reported in individuals with a personal or family history of breast and ovarian cancer, but family or functional studies were not reported to help assess the pathogenicity of this variant (Levanat et al. 2012. PubMed ID: 22366370; Alemar et al. 2017. PubMed ID: 29161300). In vitro splicing studies found that this variant did not alter splicing (Wangensteen T et al 2019. PubMed ID: 31143303). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD and is interpreted as uncertain significance by the vast majority of submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/96845/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary breast ovarian cancer syndrome

Uncertain:1

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 2336 of the BRCA2 protein (p.Arg2336Cys). This variant is present in population databases (rs431825347, gnomAD 0.01%). This missense change has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 22366370; internal data). This missense change has been observed to co-occur in individuals with a different variant in BRCA2 that has been determined to be pathogenic (internal data), but the significance of this finding is unclear. ClinVar contains an entry for this variant (Variation ID: 96845). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The cysteine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (PMID: 31143303; internal data). 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. -

Ovarian cancer

Benign:1

Jan 01, 2022

Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Benign

0.62

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0044

M_CAP

Benign

0.059

MetaRNN

Benign

0.049

T;T

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.21

PROVEAN

Benign

1.8

N;N

REVEL

Benign

0.24

Sift

Benign

0.71

T;T

Sift4G

Benign

0.15

T;T

Vest4

0.36

MutPred

0.46

Loss of disorder (P = 0.0484);Loss of disorder (P = 0.0484);

MVP

0.70

MPC

0.022

ClinPred

0.024

GERP RS

-5.6

gMVP

0.23

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00024

dbscSNV1_RF

Benign

0.020

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