13-32340570-C-G

Position:

chr13-32340570-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4BP6

The NM_000059.4(BRCA2):c.6215C>G(p.Ser2072Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000422 in 1,611,920 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. S2072F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11B:3O:1

Conservation

PhyloP100: 6.20

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 -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.32669818).

BP6

Variant 13-32340570-C-G is Benign according to our data. Variant chr13-32340570-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 38027.We mark this variant Likely_benign, oryginal submissions are: {not_provided=1, Likely_benign=3, Uncertain_significance=7}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4 linkuse as main transcript	c.6215C>G	p.Ser2072Cys	missense_variant	11/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8 linkuse as main transcript	c.6215C>G	p.Ser2072Cys	missense_variant	11/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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

GnomAD3 exomes

AF:

0.0000160

AC:

AN:

249774

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

135118

show subpopulations

Gnomad AFR exome

AF:

0.0000618

Gnomad AMR exome

AF:

0.00

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:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000404

AC:

AN:

1459818

Hom.:

Cov.:

AF XY:

0.0000441

AC XY:

AN XY:

726088

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000477

Gnomad4 OTH exome

AF:

0.0000829

GnomAD4 genome

AF:

0.0000592

AC:

AN:

152102

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000206

Hom.:

Bravo

AF:

0.0000416

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:11Benign:3Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:5

Uncertain significance, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Jun 14, 2007	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 18, 2023	This missense variant replaces serine with cysteine at codon 2072 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast and ovarian cancer (PMID: 12373604, 25136594, 21120943, 33471991) and in individuals unaffected with cancer (PMID: 33471991). This variant also has been observed in at least two individuals affected with BRCA2-associated cancers with another pathogenic variant in BRCA2, suggesting that this variant may not be the cause of observed phenotype in these individuals (ClinVar SCV000072885.9, Color internal data). In a meta-analysis of breast cancer case-control study, this variant has been observed in 3/60463 cases and 3/53458 controls (OR=0.884; 95%CI [0.178 to 4.381]) (PMID: 33471991). This variant has been identified in 8/281176 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. -
Uncertain significance, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jul 12, 2017	- -

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 29, 2024	The p.S2072C variant (also known as c.6215C>G), located in coding exon 10 of the BRCA2 gene, results from a C to G substitution at nucleotide position 6215. The serine at codon 2072 is replaced by cysteine, an amino acid with dissimilar properties. This variant (designated as 6443C>G) has been reported in a family with two diagnosed cases of breast cancer at ages 46 and 64, one case of stomach cancer diagnosed at age 45, and one case of larynx cancer (Jakubowska A et al. Br. J. Cancer. 2002 Oct;87:888-91). This variant was also identified in a cohort of 681 ancestrally diverse, healthy subjects (Bodian DL et al. PLoS One. 2014 Apr;9(4):e94554). In addition, this alteration was cited as likely benign in a multifactorial model of variant interpretation that incorporates co-segregation, family history, co-occurrence and tumor pathology and case-control data (Parsons MT et al. Hum Mutat, 2019 09;40:1557-1578). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Likely benign, criteria provided, single submitter	curation	University of Washington Department of Laboratory Medicine, University of Washington	Mar 23, 2023	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 24, 2023	This missense variant replaces serine with cysteine at codon 2072 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast and ovarian cancer (PMID: 12373604, 25136594, 21120943). This variant has been observed in at least two individuals affected with BRCA2-associated cancers with pathogenic co-variant in BRCA2 that could explain the observed phenotype (ClinVar SCV000072885.9, Color internal data). In a large breast cancer case-control study conducted by the BRIDGES consortium, this variant was reported in 3/60466 cases and 3/53461 controls (OR=0.884; 95%CI [0.178 to 4.381]) (PMID: 33471991). This variant has been identified in 8/281176 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. -

Hereditary breast ovarian cancer syndrome

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Jun 03, 2021	The BRCA2 c.6215C>G (p.Ser2072Cys) missense change has a maximum subpopulation frequency of 0.0054% in gnomAD v2.1.1 (PM2_Supporting; https://gnomad.broadinstitute.org/variant/13-32914707-C-G?dataset=gnomad_r2_1). Five of seven in silico tools predict a deleterious effect of this variant on protein function (PP3), but to our knowledge these predictions have not been confirmed by functional assays. This variant is absent in the FLOSSIES database which contains genetic variants from women older than 70 years of age who have never had cancer (https://whi.color.com/). This variant has been reported in at least three individuals with a personal or family history of breast and/or ovarian cancer (PMID: 12373604, 21120943, 25136594). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PP3 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 15, 2023	- -

not specified

Uncertain:1Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 12, 2024	Variant summary: BRCA2 c.6215C>G (p.Ser2072Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251336 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6215C>G has been reported in the literature in individuals affected with breast and/or ovarian cancer (e.g. Caux-Moncoutier_2011, Jakubowska_2002, Ruiz_2014, Coulet_2010, Konstantinopoulos_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one co-occurrence with another pathogenic variant has been reported in the BIC database (BRCA1 c.1175_1214del, p.Leu392fs), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 12373604, 20858050, 21120943, 24728327, 25136594, 25348012, 34552099, 36451132, Wu et al._I.J. Engineering and Manufacturing_2011 (No PMID)). ClinVar contains an entry for this variant (Variation ID: 38027). Based on the evidence outlined above, the variant was classified as uncertain significance. -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

Breast and/or ovarian cancer

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jun 14, 2016

- -

BRCA2-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 20, 2023

The BRCA2 c.6215C>G variant is predicted to result in the amino acid substitution p.Ser2072Cys. This variant has been reported in at least three individuals with personal and/or family histories of breast and ovarian cancers (Jakubowska et al. 2002. PubMed ID: 12373604; Table S2B, Caux-Moncoutier et al. 2011. PubMed ID: 21120943; Ruiz et al. 2014. PubMed ID: 25136594). It has also been reported in an individual with malignant peripheral nerve sheath tumors (MPNSTs) more commonly associated with NF1-related disease (Table S2B, Huang et al. 2018. PubMed ID: 29625052; see OMIM #162200). However, no functional studies have been performed to directly evaluate the pathogenicity of this variant, and it occurs within a region of the BRCA2 gene that is predicted to be tolerant to variation (Table 2, Dines et al. 2020. PubMed ID: 31911673). This variant is reported in 0.0054% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations in ClinVar ranging from uncertain significance to likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/38027/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 11, 2019

This variant is associated with the following publications: (PMID: 12373604, 24728327, 21120943, 25136594, 31131967, 29625052) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.15

CADD

Uncertain

DANN

Benign

0.97

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Pathogenic

0.98

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.33

T;T

MetaSVM

Uncertain

0.21

MutationTaster

Benign

0.67

D;D

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.74

N;N

REVEL

Uncertain

0.53

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0040

D;D

Vest4

0.34

MVP

0.94

MPC

0.14

ClinPred

0.38

GERP RS

5.8

gMVP

0.43

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

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