NM_000059.4:c.7057G>C

Variant names:

• chr13-32354910-G-C
• rs80358935
• NM_000059.4:c.7057G>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4 BP6_Very_Strong

The NM_000059.4(BRCA2):​c.7057G>C​(p.Gly2353Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000775 in 1,613,500 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 Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G2353S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000080 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Benign reviewed by expert panel U:4 B:19 O:1
• Conservation: PhyloP100: 2.91
• Publications: 28 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.29124814).
• BP6: Variant 13-32354910-G-C is Benign according to our data. Variant chr13-32354910-G-C is described in ClinVar as Benign. ClinVar VariationId is 52260.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.7057G>C	p.Gly2353Arg	missense_variant	Exon 14 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.7057G>C	p.Gly2353Arg	missense_variant	Exon 14 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.6688G>C	p.Gly2230Arg	missense_variant	Exon 14 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.7057G>C		non_coding_transcript_exon_variant	Exon 13 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152096 Hom.: 0 Cov.: 32

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: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000478 AC: 12 AN: 250872 AF XY: 0.0000369

Gnomad AFR exome AF: 0.0000619

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000617

Gnomad OTH exome AF: 0.000492

GnomAD4 exome AF: 0.0000801 AC: 117 AN: 1461404 Hom.: 0 Cov.: 31 AF XY: 0.0000908 AC XY: 66 AN XY: 727004

African (AFR) AF: 0.0000598 AC: 2 AN: 33456

American (AMR) AF: 0.0000224 AC: 1 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.00 AC: 0 AN: 86170

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000103 AC: 114 AN: 1111728

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152096 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74270

African (AFR) AF: 0.00 AC: 0 AN: 41400

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.0000900 Hom.: 0

Bravo AF: 0.0000793

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000576 AC: 7

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Uncertain:4 Benign:19 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1 Benign:5

Sep 01, 2023

Department of Medical and Surgical Sciences, University of Bologna

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

BS1(Supporting)+BS3(Strong)+BP1(Strong)+BP5(Very Strong) 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)

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jul 24, 2014

Pathway Genomics

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jun 18, 2019

Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000782

Feb 25, 2011

Sharing Clinical Reports Project (SCRP)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

not provided Benign:6

Nov 14, 2016

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The BRCA2 c.7057G>C (p.Gly2353Arg) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this substitution (SNPs&GO not captured due to low reliability index). This variant was found in 8/122392 control chromosomes at a frequency of 0.0000654, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). The variant was found in HBOC spectrum patients however, without strong evidence for pathogenicity. In fact, the variant was observed in several patients to co-occur with (potentially) pathogenic BRCA1 and BRCA2 variants such as BRCA1 c.3193_3194insG (p.Asp1065?fs); BRCA2 c.4478_4481delAAAG (p.Glu1493_Ser1494?fs); BRCA2 c.476-2A>G; BRCA1 c.IVS5+1G>A (c.212+1G>A) BRCA1 c.3612delA (p.Ala1206ProfsX4), BRCA1 c.2346dupT indicating neutrality. Furthermore, Lindor_HM_2012 reviewed a multifactorial probability based model and calculated, odds in favor of causality was 0.03 and posterior probability of being deleterious 6.12104 and classified the variant as IARC Class I (Neutral) variant. Additionally, Alsop_2012 reports LOH of the variant within a breast tumor. Moreover, several clinical diagnostic laboratories classify variant as Benign/Likely benign via ClinVar. Considering all evidence, the variant was classified as Likely Benign.

May 04, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Aug 31, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at a significant frequency in large population cohorts (Lek et al., 2016) This variant is associated with the following publications: (PMID: 29988080, 28678401, 22476429, 22678057, 10923033, 28283652, 28301460, 28263838, 21305653, 18403564, 22711857, 15026808, 20104584, 21952622, 21520273, 21671020, 21990134, 20127978, 24323938, 24728327)

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRCA2 p.Gly2353Arg variant was identified in 6 of 11570 proband chromosomes (frequency: 0.001) from individuals or families with (hereditary) breast and ovarian cancers and prostate cancer (Alsop 2012, Baila 2011, Borg 2010, Claes 2004, Kote-Jarai 2011, Morgan 2010). In a functional assay that evaluated the effect of the transient overexpression of the p.Gly2353Arg variant on spontaneous homologous recombination (HR) in a HeLa cell line, the variant increased HR as much as a pathogenic variant G2748D, which led the authors to classify it as possibly pathogenic (Baila 2011). However Lindor et al (2012) found the variant to be neutral based on a posterior probability model which combines segregation data, co-occurrence with pathogenic mutations, personal and family history of cancer and histopathology to determine a variant’s pathogenicity, suggesting a limited specificity of the recombination assay. Guidugli et al. 2014 also report the p.Gly2353Arg variant as “not pathogenic” citing that the Baila study does not measure a known BRCA2 function but rather an error prone repair mechanism such as single strand annealing in the absence of functional BRCA2 and therefore question the application of their assay to measure a BRCA2 variant’s function. The variant was identified in dbSNP (ID: rs80358935) with “Other” allele, Clinvitae database (with conflicting classifications), the ClinVar database (with conflicting interpretations of pathogenicity: classified as benign by Invitae, Pathway Genomics and Sharing Clinical Reports Project (derived from Myriad reports), as likely benign by Ambry Genetics, Illumina, and GeneDx, and as uncertain significance by BIC), GeneInsight COGR database (classifications uncertain significance, benign and unclassified “by 3 clinical laboratories), the BIC database (19x with unknown clinical importance, classification pending), the Fanconi Anemia Mutation Database-LOVD (1x as “probably affects function/not classified”) and UMD (9x with a ”unclassified variant” classification, and co-occurring with 2 pathogenic BRCA1 mutations (c.212+1G>A and c.3612delA, p.Ala1206ProfsX4) increasing the likelihood that the p.Gly2353Arg variant does not have clinical significance. This variant was identified in the NHLBI GO Exome Sequencing Project in 1 of 8600 European American alleles, (frequency: 0.00012) and in the Exome Aggregation Consortium database (August 8, 2016) in 7 of 121030 chromosomes (freq. 00006) and in the Genome Aggregation Consortium (October 3, 2017) in the following populations: Other in 1 of 5472 chromosomes (freq. 0002), Latino in 1 of 33564 chromosomes (freq. 0.00003), and European (Non-Finnish) in 9 of 111462 chromosomes (freq. 0.00008), African in 1 of 15288 chromosomes (freq. 0.00007), but was not seen in the Ashkenazi Jewish, East Asian, European (Finnish), or South Asian populations, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. Myriad classifies this as a polymorphism (personal communication). The variant was also identified by our laboratory in 3 individuals with breast cancer. The p.Gly2353 residue is not conserved in mammals and 3 out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is cl

not specified Uncertain:2 Benign:2 Other:1

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Mar 16, 2018

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Clinvar: 3 labs classify as LB/Ben, 2 as VUS; ExAC: 5/66708 European chromosomes

Hereditary cancer-predisposing syndrome Benign:3

Jan 29, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

Mar 02, 2016

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 20, 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.

Breast and/or ovarian cancer Uncertain:1 Benign:1

May 10, 2012

Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Mar 09, 2021

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Fanconi anemia complementation group D1 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Hereditary breast ovarian cancer syndrome Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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	0.15
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0	.;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.0	.;.
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.29	T;T
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	0.0	.;.
PhyloP100		2.9
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.5	N;N
REVEL	Uncertain	0.40
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.027	D;D
Vest4		0.33
ClinPred		0.33	T
GERP RS		3.0
gMVP		0.23
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs80358935; hg19: chr13-32929047;