13-32398388-C-T

Position:

chr13-32398388-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_ModerateBP6_Very_Strong

The NM_000059.4(BRCA2):c.9875C>T(p.Pro3292Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000062 in 1,614,098 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 (★★★). Synonymous variant affecting the same amino acid position (i.e. P3292P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000059 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:10B:15

Conservation

PhyloP100: 2.19

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 Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1849584).

BP6

Variant 13-32398388-C-T is Benign according to our data. Variant chr13-32398388-C-T is described in ClinVar as [Benign]. Clinvar id is 52910.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4 linkuse as main transcript	c.9875C>T	p.Pro3292Leu	missense_variant	27/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8 linkuse as main transcript	c.9875C>T	p.Pro3292Leu	missense_variant	27/27	5	NM_000059.4	ENSP00000369497	A2

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000717

AC:

AN:

251176

Hom.:

AF XY:

0.0000737

AC XY:

AN XY:

135736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.000489

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000588

AC:

AN:

1461862

Hom.:

Cov.:

AF XY:

0.0000454

AC XY:

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.000478

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.000277

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.0000234

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.0000963

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000164

Hom.:

Bravo

AF:

0.000178

ExAC

AF:

0.0000741

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Uncertain:10Benign:15

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:1Benign:6

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -
Likely benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Jun 05, 2008	- -
Likely benign, criteria provided, single submitter	clinical testing	Michigan Medical Genetics Laboratories, University of Michigan	Apr 21, 2016	- -
Benign, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
Benign, no assertion criteria provided	clinical testing	Department of Medical and Surgical Sciences, University of Bologna	Sep 01, 2023	BS1(Strong)+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) -
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 = 0.000108 -

not provided

Uncertain:4Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 08, 2020	This variant is associated with the following publications: (PMID: 32444794, 31409081, 31509718, 30199306, 30287823, 30400234, 29802286, 31131967, 29126202, 28814288, 28477318, 27907908, 27211102, 26566862, 26577449, 24372583, 25589618, 26740942, 19540122, 24323938, 18593900, 15800615, 20104584, 23704879) -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 03, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 23, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 14, 2017	The BRCA2 c.9875C>T; p.Pro3292Leu variant is described in the medical literature in individuals and families with breast cancer (Borg 2010, Francies 2015, Riahi 2015, Chao2016). However, the variant was also published in an individual with Fanconi anemia who also carried two nonsense variants in the FANCC gene (Nicchia 2015). The variant is listed in the ClinVar database as both a variant of uncertain significance and as likely benign/benign (Variation ID: 52910). The variant is listed in the dbSNP variant database (rs56121817) and in the Genome Aggregation Database in 20/245936 alleles. The proline at this position is conserved across species and computational algorithms (PolyPhen2, SIFT) predict this variant is deleterious. While in silico studies imply this variant may impact function (Tram 2013) functional studies show that this variant has no effect on at least some functions (Eashi 2005, Hucl 2008). Considering available information, this variant cannot be classified with certainty. References: Borg A et al. Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study. Hum Mutat. 2010 Mar;31(3):E1200-40. Chao A et al. Prevalence and clinical significance of BRCA1/2 germline and somatic mutations in Taiwanese patients with ovarian cancer. Oncotarget. 2016 Dec 20;7(51):85529-85541. Esashi F et al. CDK-dependent phosphorylation of BRCA2 as a regulatory mechanism for recombinational repair. Nature. 2005 Mar 31;434(7033):598-604. Francies FZ et al. BRCA1, BRCA2 and PALB2 mutations and CHEK2 c.1100delC in different South African ethnic groups diagnosed with premenopausal and/or triple negative breast cancer. BMC Cancer. 2015 Nov 17;15:912. Hucl T et al. A syngeneic variance library for functional annotation of human variation: application to BRCA2. Cancer Res. 2008 Jul 1;68(13):5023-30. Nicchia E et al. Identification of point mutations and large intragenic deletions in Fanconi anemia using next-generation sequencing technology. Mol Genet Genomic Med. 2015 Jul 2;3(6):500-12. Riahi A et al. Mutation spectrum and prevalence of BRCA1 and BRCA2 genes in patients with familial and early-onset breast/ovarian cancer from Tunisia. Clin Genet. 2015 Feb;87(2):155-60. Tram E et al. Missense variants of uncertain significance (VUS) altering the phosphorylation patterns of BRCA1 and BRCA2. PLoS One. 2013 May 21;8(5):e62468. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 19, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 29, 2017	- -

not specified

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 06, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 20, 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: Reported in 1 Br.Ca. patient, functional study shows potential impact (not enough to go above VUS); ClinVar: 4 VUS, 2 LB -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 18, 2019	Variant summary: BRCA2 c.9875C>T (p.Pro3292Leu) results in a non-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 8.9e-05 in 247930 control chromosomes (gnomAD and publication). This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (8.9e-05 vs 0.00075) however, the variant could still represent a rare polymorphism. c.9875C>T has been reported in the literature in individuals affected with breast and/or ovarian cancer, sarcoma, metastatic castration-resistant prostate cancer and pancreatic ductal adenocarcinoma (Abulkhair_2018, Diaz-Zabala_2018, Takeuchi_2018, Annala_2017, Barrios_2017, Ballinger_2016, Chao_2016, Francies_2015, Riahi_2015, Borg_2010). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variants have been reported (BRCA2 c.3922G>T, p.Glu1308X; BRCA2 c.9117G > A, p.Pro3039Pro; BRCA2 9502delT, c.9274delT, p.Tyr3092Ilefs)(Barrios_2017, ClinVar, BIC database), providing supporting evidence for a benign role. Furthermore, in a Fanconi anemia patient carrying this variant, variants were detected in FANCC gene (c.37C>T, p.Gln13X; c.1069C>T, p.Gln357X) (Nicchia_2015), providing supporting evidence for a benign role in this specific case. Experimental evidence evaluating an impact on protein function reported the variant as not being disruptive to the interaction of BRCA2 with RAD51, RAD51 foci formation was not significantly impaired following DNA damage induction and no significant increase in sensitivity to mitomycin C and etoposide was observed (Esashi _2005, Hucl _2008). Nine ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance (5x), likely benign (3x) and once as benign. Based on the evidence outlined above, the variant was classified as benign. -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Dec 13, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 04, 2021	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 30, 2016	- -

Hereditary breast ovarian cancer syndrome

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	Apr 19, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -

Familial cancer of breast

Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Center for Precision Medicine, Meizhou People's Hospital

- -

Fanconi anemia complementation group D1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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. -

Malignant tumor of breast

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The BRCA2 p.Pro3292Leu variant was identified in 6 of 7398 proband chromosomes (frequency: 0.0008) from individuals or families with breast, ovarian or pancreatic cancer and was not identified in 874 control chromosomes from healthy individuals (Borg 2010, Capanu 2011, Francies 2015, Riahi 2015, Takeuchi 2018). The variant was also identified in dbSNP (ID: rs56121817) as "With other allele", ClinVar (classified as benign by Invitae; as likely benign by GeneDx, SCRP and three other submitters; as uncertain significance by six submitters), LOVD 3.0 (8x), and in UMD-LSDB (14X as unclassified variant). The variant was identified in control databases in 20 of 245936 chromosomes at a frequency of 0.00008 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 2 of 5478 chromosomes (freq: 0.0004), Latino in 2 of 33562 chromosomes (freq: 0.00006), European in 6 of 111458 chromosomes (freq: 0.00005), Ashkenazi Jewish in 1 of 9844 chromosomes (freq: 0.0001), East Asian in 9 of 17246 chromosomes (freq: 0.0005), while the variant was not observed in the African, Finnish, and South Asian populations. In function studies Huci et al found that the p.Pro3292Leu variant was not sensitive to mitomycin C and etoposide induced DNA damage compared to wildtype unlike a truncating variant that was studied, moreover BRCA2/RAD51 foci formed normally with the variant present suggesting that the variant does not have clinical significance (Huci 2008). However, based on the location of the variant it is predicted to disrupt the sequence motif of the CDK2 kinase and affects interaction with RAD51 (Krassowski 2018, Tram 2013). Although the p.Pro3292 residue is not conserved in mammals and other organisms, computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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 classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.16

CADD

Uncertain

DANN

Uncertain

1.0

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.87

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.18

T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-2.9

D;D

REVEL

Benign

0.22

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0060

D;D

Vest4

0.46

MVP

0.88

MPC

0.16

ClinPred

0.44

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

gMVP

0.48

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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