13-32356496-C-T

Position:

chr13-32356496-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4_StrongBP6

The NM_000059.4(BRCA2):c.7504C>T(p.Arg2502Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000173 in 1,614,150 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict 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. R2502H) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00087 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:17

Conservation

PhyloP100: 0.109

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.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 16 uncertain in NM_000059.4

BP4

Computational evidence support a benign effect (MetaRNN=0.014025956).

BP6

Variant 13-32356496-C-T is Benign according to our data. Variant chr13-32356496-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 41563.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Benign=7, Likely_benign=8}. Variant chr13-32356496-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4 linkuse as main transcript	c.7504C>T	p.Arg2502Cys	missense_variant	15/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8 linkuse as main transcript	c.7504C>T	p.Arg2502Cys	missense_variant	15/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes

AF:

0.000874

AC:

133

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00306

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000294

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000270

AC:

AN:

251420

Hom.:

AF XY:

0.000206

AC XY:

AN XY:

135876

show subpopulations

Gnomad AFR exome

AF:

0.00338

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000101

AC:

148

AN:

1461852

Hom.:

Cov.:

AF XY:

0.0000935

AC XY:

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.00287

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.0000270

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.000867

AC:

132

AN:

152298

Hom.:

Cov.:

AF XY:

0.000846

AC XY:

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.00303

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000240

Hom.:

Bravo

AF:

0.00113

ESP6500AA

AF:

0.00340

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000296

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:17

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:3

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The BRCA2 p.Arg2502Cys variant was identified in 1 of 1144 proband chromosomes (frequency: 0.0.001) from individuals or families with cancer syndromes (Johnston 2012). The variant was also identified by our laboratory in 1 individual with breast cancer. The variant was identified in dbSNP (ID: rs55716624 â€šÃ„ÃºWith Uncertain significance alleleâ€šÃ„Ã¹, with a minor allele frequency of 0.0004 (2/5000 chromosomes tested in 1000 Genomes Project), NHLBI Exome Sequencing Project (Exome Variant Server) in 15 of 4406 African Americans (frequency: 0.0034) and not found in European Americans, Exome Aggregation Consortium database (March 14, 2016) in 36 of 121024 chromosomes (frequency:0.003) from a population of African (30/10322), European (Non-Finnish-4/66524), Latino (1/11538) individuals and not in East Asian , South Asian and European (Finnish) or Other individuals. The p.Arg2502Cys variant was also identified in HGMD, LOVD (2x as unknown), classified as an Uncertain significance variant by 6 separate submitters to the ClinVar database (the Sharing Clinical Reports Project derived from Myriad reports, GeneDX, BIC, Ambry Genetics, CSER_CC_NCGL, Biesecker Laboratory â€šÃ„Ã¬ ClinSeq Project_NHGRI), GeneInsight COGR 1x (classified as uncertain by a clinical laboratory), the BIC database (17x with unknown clinical importance), and UMD (6x as an uncertain variant). Note the variant co-occurred 2x with 2 other variants of unknown significance i.e. c.1798T>C, p.Tyr600His VUS and c.IVS10+9delGT VUS. The p.Arg2502 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. The p.Arg2502Cys variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In addition, an assessment of 1,433 missense variants of unknown clinical significance, a likelihood ratio was computed based on a hypothesis that the variants were equivalent to an average deleterious mutation compared with neutral with respect to odds risk to other factors such as family history and co-occurrence. The likelihood ratios derived from each component were combined to provide an overall assessment for each VUS. The combined odds ratio for the variant was 21:1 and predicted causal, an odds ratio of 100:1 being neutral (Easton 2007). In another study (Karchin 2008), the authors are in disagreement with the conclusion of the Easton study. They have presented a new computational approach for analyzing the impact of missense changes in the DNA-binding domains of the cancer susceptibility protein BRCA2 that uses information from protein sequence, structure, and sequence conservation. They concluded the 2502Cys variant as neutral. 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. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 11, 2016	Variant summary: Variant affects a non-conserved nucleotide and results in a replacement of a large size and basic Arginine (R) with a medium size and polar Cysteine (C). 4/5 in silico tools predict the variant to be benign. It was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.029%. It is most prevalent in the African subpopulation with an observed allele frequency of 0.29% which exceeds the maximal expected allele frequency of a disease causing BRCA2 allele (0.075%) indicating the variant to be benign. The variant was also observed in HBOC spectrum patients, however without strong evidence for pathogenicity. A functional study reported the variant not to have an effect on normal splicing. Moreover, BIC reports co-occurrence with multiple pathogenic BRCA1 variants c.3764_3765insA (p.Asn1255fsX12), and c.5324T>G (p.Met1775Arg) and c. 5074G>A (p.Asp1692Asn) further supporting a benign impact. Clinical diagnostic centers classify variant as Uncertain/Likely Benign/Benign via ClinVar (without evidence to independently evaluate). Considering all evidence, the variant was classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 15, 2022	- -
Uncertain significance, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	BRCA2: BP4, BS1 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 05, 2014	- -

Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:3Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Apr 12, 2016	- -
Benign, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Feb 02, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -
Uncertain significance, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Feb 09, 2007	- -

not specified

Uncertain:1Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 23, 2016	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: Frequency; ClinVar: 2 LB, 7 VUS -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 13, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 30, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 18, 2019	- -

Hereditary cancer-predisposing syndrome

Benign:4

Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Jan 05, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 22, 2020	This alteration is classified as 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. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 24, 2016	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	May 17, 2021	- -

Hereditary breast ovarian cancer syndrome

Benign:4

Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Dec 03, 2020	The BRCA2 c.7504C>T (p.Arg2502Cys) missense change has a maximum subpopulation frequency of 0.32% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/13-32930633-C-T). This frequency is higher than would be expected for a pathogenic variant in BRCA2 (BS1; PMID: 28166811). This variant affects a nucleotide that is not highly conserved and is predicted to be benign by multiple in silico algorithms (BP4). In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria: BS1, BP4. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	curation	German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	Oct 19, 2023	(BA1, BS3, BP4_strong). According to the ACMG standard criteria we chose these criteria: BP4 (strong benign): Bayes Del noAF (-0.0527), BS3 (strong benign): Richardson et al., 2021: neutral / final classification: benign (BA1, BS3, BP4_strong), BA1 (stand-alone benign): gnomAD: AF AFR: 0.003065 -

Breast and/or ovarian cancer

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Dec 05, 2022	- -
Uncertain significance, criteria provided, single submitter	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	Low GERP score may suggest that this variant may belong in a lower pathogenicity class -

BRCA2-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 01, 2022

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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

-0.050

CADD

Benign

8.7

DANN

Benign

0.93

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.059

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.014

T;T

MetaSVM

Benign

-0.76

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.18

PROVEAN

Benign

-0.92

N;N

REVEL

Uncertain

0.52

Sift

Benign

0.12

T;T

Sift4G

Benign

0.12

T;T

Vest4

0.19

MVP

0.75

MPC

0.022

ClinPred

0.014

GERP RS

0.57

gMVP

0.21

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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