13-32340292-C-G

Position:

chr13-32340292-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM5BP6

The NM_000059.4(BRCA2):c.5937C>G(p.Ser1979Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000316 in 1,613,800 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. S1979?) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10B:2

Conservation

PhyloP100: 0.604

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 Uncertain_significance. Variant got 1 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr13-32340289-TAG-TT is described in Lovd as [Pathogenic].

BP6

Variant 13-32340292-C-G is Benign according to our data. Variant chr13-32340292-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 38009.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=8}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4 linkuse as main transcript	c.5937C>G	p.Ser1979Arg	missense_variant	11/27	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.5937C>G	p.Ser1979Arg	missense_variant	11/27	5	NM_000059.4	ENSP00000369497	A2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

250684

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135746

show subpopulations

Gnomad AFR exome

AF:

0.0000632

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:

0.0000441

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000322

AC:

AN:

1461668

Hom.:

Cov.:

AF XY:

0.0000413

AC XY:

AN XY:

727136

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000405

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152132

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.0000483

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000565

Hom.:

Bravo

AF:

0.0000264

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:4

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Feb 20, 2004	- -
Uncertain significance, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Feb 15, 2007	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 11, 2024	This missense variant replaces serine with arginine at codon 1979 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 an individual affected with breast cancer (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_002908) and an individual with personal or family history of breast or ovarian cancer (PMID 21120943). This variant has been identified in 6/250684 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, criteria provided, single submitter	clinical testing	Counsyl	Dec 11, 2015	- -

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 20, 2024	The p.S1979R variant (also known as c.5937C>G), located in coding exon 10 of the BRCA2 gene, results from a C to G substitution at nucleotide position 5937. The serine at codon 1979 is replaced by arginine, an amino acid with dissimilar properties. In one study, this variant was observed in 1/1525 unrelated patients who had BRCA1/2 genetic testing due to a personal and/or family history suspicious for Hereditary Breast and/or Ovarian Cancer syndrome (Caux-Moncoutier V et al. Hum Mutat, 2011 Mar;32:325-34). In a study of whole-exome sequencing in patients with features of Cowden syndrome (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS) and negative PTEN testing, this alteration was identified in 0/87 patients with CS or BRRS and 1/3476 patients from The Cancer Genome Atlas (Yehia L et al. PLoS Genet, 2018 04;14:e1007352). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 08, 2023	This missense variant replaces serine with arginine at codon 1979 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 an individual affected with breast cancer (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_002908) and an individual with personal or family history of breast or ovarian cancer (PMID 21120943). This variant has been identified in 6/250684 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. -
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). -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 27, 2024	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 6165C>G; This variant is associated with the following publications: (PMID: 18724707, 21120943, 26992456, 25348012, 31131967, 31911673, 29884841, 32377563, 31853058, 29684080, 9002670, 22193408) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 23, 2023	In the published literature, this variant has been reported in individuals with a personal or family history of breast and/or ovarian cancer (PMIDs: 21120943 (2011), 33471991 (2021) see also LOVD (https://databases.lovd.nl/shared/variants/BRCA2)). This variant has also been reported in one or more individuals with thyroid carcinoma (PMID: 29684080 (2018)). The frequency of this variant in the general population, 0.000044 (5/113458 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jun 17, 2024

Variant summary: BRCA2 c.5937C>G (p.Ser1979Arg) results in a non-conservative amino acid change located in the seventh BRCA2 repeat (IPR002093) of the encoded protein sequence. The BRCA2 repeat region consists of eight repeats (BRC) that are critical for binding to RAD51, where BRC1-4 and BRC7-8 are highly conserved and participate in Rad51 binding [PMID 10551859]. 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 2.4e-05 in 250684 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5937C>G has been reported in the literature in an individual with a personal and/or family history of breast and/or ovarian cancer (Caux-Moncoutier_2011), however, without strong evidence for causality (i.e. no cosegregation- and co-occurrence data were provided). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. 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: 21120943, 25348012, 18724707, 26992456). ClinVar contains an entry for this variant (Variation ID: 38009). Based on the evidence outlined above, the variant was classified as uncertain significance. -

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

Feb 05, 2020

- -

Hereditary breast ovarian cancer syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 14, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Uncertain

0.095

BayesDel_noAF

Uncertain

0.080

CADD

Benign

DANN

Uncertain

1.0

Eigen

Uncertain

0.20

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.89

M_CAP

Uncertain

0.20

MetaRNN

Uncertain

0.65

D;D

MetaSVM

Benign

-0.34

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.42

PROVEAN

Pathogenic

-4.5

D;D

REVEL

Uncertain

0.56

Sift

Uncertain

0.0050

D;D

Sift4G

Uncertain

0.014

D;D

Vest4

0.61

MutPred

0.59

Gain of MoRF binding (P = 0.0488);Gain of MoRF binding (P = 0.0488);

MVP

0.87

MPC

0.099

ClinPred

0.63

GERP RS

3.8

gMVP

0.52

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