13-32354874-C-T

Position:

chr13-32354874-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000059.4(BRCA2):c.7021C>T(p.Arg2341Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000125 in 1,438,230 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R2341R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9B:2

Conservation

PhyloP100: -0.0330

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 Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.25494078).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4 linkuse as main transcript	c.7021C>T	p.Arg2341Cys	missense_variant	14/27	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.7021C>T	p.Arg2341Cys	missense_variant	14/27	5	NM_000059.4	ENSP00000369497.3	P51587
BRCA2	ENST00000530893.7 linkuse as main transcript	c.6652C>T	p.Arg2218Cys	missense_variant	14/27	1		ENSP00000499438.2	A0A590UJI7
BRCA2	ENST00000614259.2 linkuse as main transcript	n.7021C>T		non_coding_transcript_exon_variant	13/26	2		ENSP00000506251.1	A0A7P0TAP7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

250562

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135728

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000353

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000125

AC:

AN:

1438230

Hom.:

Cov.:

AF XY:

0.0000140

AC XY:

AN XY:

716814

show subpopulations

Gnomad4 AFR exome

AF:

0.0000304

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000506

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.0000110

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000624

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 24, 2023	The p.R2341C variant (also known as c.7021C>T), located in coding exon 13 of the BRCA2 gene, results from a C to T substitution at nucleotide position 7021. The arginine at codon 2341 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been detected in a suspected HBOC family and in multiple patients diagnosed with breast cancer (Warren CR et al. Exp. Cell Res. 2011 Sep; 317:2099-109; Wong-Brown MW et al. Breast Cancer Res. Treat. 2015 Feb; 150(1):71-80; Penkert J et al. Breast Cancer Res, 2018 08;20:87). This alteration has also been detected in a cohort of 727 patients with personal and family history of pancreatic cancer (Zhen DB et al. Genet. Med., 2015 Jul;17:569-77). Additionally, this alteration was observed in with an allele frequency of 0.00014 in 7,051 unselected female breast cancer patients and was observed with an allele frequency of 0 in 11,241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083) and in 1/1358 non-cancer control individuals and in 0/57 cases, in a study looking at cancer predisposition mutations in patients with cutaneous melanoma and a history of at least two additional non-cutaneous melanoma primary cancers (Pritchard AL et al. PLoS One, 2018 Apr;13:e0194098). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Nov 03, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 09, 2023	This missense variant replaces arginine with cysteine at codon 2341 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). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in individuals affected with breast cancer (PMID: 21741379, 25682074, 30086788, 30287823), pancreatic cancer (PMID: 25356972), and prostate cancer (PMID: 31214711). This variant has been identified in 6/250562 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. -

Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Jul 01, 2008	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 27, 2017	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Sep 03, 2021

Variant summary: BRCA2 c.7021C>T (p.Arg2341Cys) results in a non-conservative amino acid change located in the Linker region (Warren_2011) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.2e-05 in 273044 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7021C>T has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Warren_ 2011, Wong-Brown_2015, Momozawa_2018) and was also found in one patient with pancreatic cancer (Zhen_2014). These reports however do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with pathogenic variants have been reported in UMD database (BRCA1 c.3048_3067del; p.Asn1018HisfsX3 and BRCA2 c.3744_3747delTGAG ; p.Ser1248ArgfsX10), providing supporting evidence for a benign role. The variant was found to have no effect on splicing (Wai_2020). Five other ClinVar submitters (evaluation after 2014) with four citing the variant as uncertain significance and one citing at likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

BRCA2-related cancer predisposition

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Jul 20, 2024

This missense variant replaces arginine with cysteine at codon 2341 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. This variant did not impact function in a high throughput multiplexed NGS-based functional assay in mouse embryonic stem cells (PMID: 37922907). This variant has been observed in individuals affected with breast cancer (PMID: 21741379, 25682074, 30086788, 30287823), pancreatic cancer (PMID: 25356972), and prostate cancer (PMID: 31214711). This variant has been identified in 6/250562 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 provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 19, 2023

In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer or pancreatic cancer, but also in unaffected controls (Warren et al., 2011; Wong-Brown et al., 2015; Zhen et al., 2015; Momozawa et al., 2018; Penkert et al., 2018; Pritchard et al., 2018); Also known as 7249C>T; This variant is associated with the following publications: (PMID: 20858050, 21741379, 25682074, 25356972, 31131967, 30287823, 30086788, 29641532, 32123317, 29884841, 32377563) -

Familial cancer of breast

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 18, 2024

- -

Breast and/or ovarian cancer

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research

May 10, 2012

- -

Hereditary breast ovarian cancer syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 14, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Uncertain

0.020

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

DANN

Benign

0.92

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.11

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.25

T;T

MetaSVM

Benign

-0.46

PrimateAI

Benign

0.20

PROVEAN

Benign

-1.6

N;N

REVEL

Uncertain

0.53

Sift

Benign

0.044

D;D

Sift4G

Uncertain

0.035

D;D

Vest4

0.26

MutPred

0.51

Loss of disorder (P = 0.036);Loss of disorder (P = 0.036);

MVP

0.92

MPC

0.022

ClinPred

0.30

GERP RS

-2.2

gMVP

0.37

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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