NM_000059.4:c.7021C>T

Variant names:

• chr13-32354874-C-T
• rs41293505
• NM_000059.4:c.7021C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM1 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. 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. R2341H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:2
• Conservation: PhyloP100: -0.0330
• Publications: 21 publications found

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 Gene-Disease associations (from GenCC):

• breast-ovarian cancer, familial, susceptibility to, 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• Fanconi anemia complementation group D1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
• pancreatic cancer, susceptibility to, 2

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary breast ovarian cancer syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• medulloblastoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 34 uncertain in NM_000059.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.25494078).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000059.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA2	NM_000059.4	MANE Select	c.7021C>T	p.Arg2341Cys	missense	Exon 14 of 27	NP_000050.3
	BRCA2	NM_001432077.1		c.7021C>T	p.Arg2341Cys	missense	Exon 14 of 27	NP_001419006.1
	BRCA2	NM_001406720.1		c.7021C>T	p.Arg2341Cys	missense	Exon 14 of 27	NP_001393649.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA2	ENST00000380152.8	TSL:5 MANE Select	c.7021C>T	p.Arg2341Cys	missense	Exon 14 of 27	ENSP00000369497.3
	BRCA2	ENST00000544455.6	TSL:1	c.7021C>T	p.Arg2341Cys	missense	Exon 14 of 27	ENSP00000439902.1
	BRCA2	ENST00000530893.7	TSL:1	c.6652C>T	p.Arg2218Cys	missense	Exon 14 of 27	ENSP00000499438.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 250562 AF XY: 0.0000295

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000125 AC: 18 AN: 1438230 Hom.: 0 Cov.: 30 AF XY: 0.0000140 AC XY: 10 AN XY: 716814

African (AFR) AF: 0.0000304 AC: 1 AN: 32890

American (AMR) AF: 0.0000224 AC: 1 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25976

East Asian (EAS) AF: 0.0000506 AC: 2 AN: 39550

South Asian (SAS) AF: 0.00 AC: 0 AN: 85748

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5720

European-Non Finnish (NFE) AF: 0.0000110 AC: 12 AN: 1090624

Other (OTH) AF: 0.00 AC: 0 AN: 59620

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000360 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:3

Jun 26, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Nov 03, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

Feb 08, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:2

Jul 01, 2008

Sharing Clinical Reports Project (SCRP)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Dec 27, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

BRCA2-related cancer predisposition Uncertain:2

Jul 20, 2024

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 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.

Oct 08, 2024

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Uncertain:1

Sep 03, 2021

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.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.

not provided Uncertain:1

Jul 19, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 18, 2024

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breast and/or ovarian cancer Benign:1

May 10, 2012

Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Hereditary breast ovarian cancer syndrome Benign:1

Jan 05, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.020	T
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	19
DANN	Benign	0.92
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.11	N
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.46	T
PhyloP100		-0.033
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.53
Sift	Benign	0.044	D
Sift4G	Uncertain	0.035	D
Vest4		0.26
MutPred		0.51		Loss of disorder (P = 0.036)
MVP		0.92
MPC		0.022
ClinPred		0.30	T
GERP RS		-2.2
gMVP		0.37
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
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

Other links and lift over

dbSNP: rs41293505; hg19: chr13-32929011;