rs80358921

Positions:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PP3_ModerateBP6_Very_Strong

The NM_000059.4(BRCA2):c.6953G>A(p.Arg2318Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000187 in 1,607,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R2318G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:4B:11

Conservation

PhyloP100: 6.50

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 -6 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.884

BP6

Variant 13-32346842-G-A is Benign according to our data. Variant chr13-32346842-G-A is described in ClinVar as [Benign]. Clinvar id is 52225.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4 linkuse as main transcript	c.6953G>A	p.Arg2318Gln	missense_variant	13/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8 linkuse as main transcript	c.6953G>A	p.Arg2318Gln	missense_variant	13/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151976

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

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:

0.00000801

AC:

AN:

249792

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135090

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000291

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:

0.00000884

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1455858

Hom.:

Cov.:

AF XY:

0.0000249

AC XY:

AN XY:

724304

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000235

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151976

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74222

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000656

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

Alfa

AF:

0.0000308

Hom.:

Bravo

AF:

0.00000756

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Benign

Submissions summary: Uncertain:4Benign:11

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:1Benign:3

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -
Benign, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Jun 18, 2019	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 = 0.000238 -
Likely benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Mar 29, 2012	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Breast and/or ovarian cancer

Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jul 03, 2021	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Department of Pathology and Molecular Medicine, Queen's University	Apr 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 22, 2022	Variant summary: BRCA2 c.6953G>A (p.Arg2318Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250152 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6953G>A has been reported in the literature as a VUS in individuals affected with/undergoing testing for breast and/or ovarian cancer (example, Chenevix-Trench_2018, Hondow_2011, Kote-Jarai_2011, Alsop_2012). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Multifactorial probability models have reported a neutral outcome (Lindor_2012). Co-occurrences with other pathogenic variant(s) have been reported in various databases and in the literature (BRCA2 c.2330dup, p.Asp777fs; BRCA1 c.2071delA, p.Arg691fs), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple clinical diagnostic laboratories and an expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and a predominant consensus as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 05, 2019	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 10923033, 21702907, 25452441, 17972171, 25348012, 27153395, 21990134, 16489001, 21990165, 21741379, 22711857, 26941049, 21952622, 25479140, 31131967) -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 07, 2023	- -

Hereditary cancer-predisposing syndrome

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 27, 2018	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. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 02, 2016	- -

Malignant tumor of breast

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The BRCA2 p.Arg2318Gln variant was identified in 5 of 12202 proband chromosomes (frequency: 0.0004) from individuals or families with breast, ovarian, prostate, and pancreatic cancer and was not identified in 360 control chromosomes from healthy individuals (Alsop_2012, Kote-Jarai_2011, Couch_2015, Dos Santos Vidal_2016, Grant_2015, Chenevix-Trench_2006). The variant was also identified in the following databases: dbSNP (ID: rs80358921) as â€šÃ„ÃºWith other alleleâ€šÃ„Ã¹, ClinVar and Clinvitae (6x as likely benign by Ambry Genetics, COGR, Invitae, SCRP and as uncertain significance by GeneDx, BIC), LOVD 3.0 (5x), UMD-LSDB (5 entries as uncertain significance and in one case the p.Arg2318Gln variant has been reported as co-occurring with a pathogenic variant of BRCA2 gene (c.2330dup, p.Asp777GlnfsX11), BIC Database (4x), ARUP Laboratories (1x as â€šÃ„Ãºclass 2-likely not pathogenic or of little clinical significanceâ€šÃ„Ã¹). The variant was not identified in Cosmic, MutDB and Zhejiang Colon Cancer Database. The variant was identified in control databases in 2 of 244730 chromosomes at a frequency of 0.000008 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: Latino in 1 of 33426 chromosomes (freq: 0.00003), European Non-Finnish in 1 of 111204 chromosomes (freq: 0.000009); but not observed in the African, Other, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. A functional study showed decreased cell survival and a higher rate of apoptosis in response to cisplatin as compared to wild-type (Warren_2011). The p.Arg2318 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of 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. This variant is classified as a variant of uncertain significance. -

BRCA2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 14, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary breast ovarian cancer syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 24, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

DANN

Pathogenic

1.0

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Uncertain

0.96

M_CAP

Pathogenic

0.32

MetaRNN

Pathogenic

0.88

D;D

MetaSVM

Uncertain

0.70

MutationTaster

Benign

0.99

D;D

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.0

N;N

REVEL

Pathogenic

0.73

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Vest4

0.81

MutPred

0.80

Gain of ubiquitination at K2316 (P = 0.0485);Gain of ubiquitination at K2316 (P = 0.0485);

MVP

0.97

MPC

0.17

ClinPred

0.99

GERP RS

5.0

gMVP

0.48

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