rs138489917

Positions:

Variant summary

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

The NM_000059.4(BRCA2):c.5495C>A(p.Ser1832Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,613,294 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:7

Conservation

PhyloP100: -0.122

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=0.339904).

BP6

Variant 13-32339850-C-A is Benign according to our data. Variant chr13-32339850-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 91415.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4 linkuse as main transcript	c.5495C>A	p.Ser1832Tyr	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.5495C>A	p.Ser1832Tyr	missense_variant	11/27	5	NM_000059.4	ENSP00000369497	A2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000576

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000160

AC:

AN:

250668

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135568

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.00000548

AC:

AN:

1461140

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

726766

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:

0.00

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000576

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 25, 2021	The BRCA2 c.5495C>A; p.Ser1832Tyr variant (rs138489917) has been reported in the literature in multiple individuals with breast cancer, but without evidence of pathogenicity (Borg 2010, Momozawa 2018). This variant is reported in ClinVar (Variation ID: 91415), and observed in the East Asian population at an overall frequency of 0.021% (4/18860 alleles) in the Genome Aggregation Database. The serine at codon 1832 is weakly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.409). This variant has been detected in an individual who also harbored a pathogenic BRCA1 variant, suggesting that BRCA2 p.Ser1832Tyr does not contribute to hereditary breast and ovarian cancer risk. However, due to the lack of clinical and functional data regarding this variant, its clinical significance cannot be determined 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. PMID: 20104584. Momozawa Y et al. Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls. Nat Commun. 2018 Oct 4;9(1):4083. doi: 10.1038/s41467-018-06581-8. PMID: 30287823. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 04, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast cancer (Borg et al., 2010; Momozawa et al., 2018; Dorling et al., 2021); Also known as 5723C>A; This variant is associated with the following publications: (PMID: 20104584, 28222693, 30311378, 30212499, 30287823, 31131967, 21520273, 32377563, 29884841, 33471991) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 31, 2023	In the published literature, the variant has been reported in individuals affected with breast cancer (PMIDs: 33471991 (2021), 30287823 (2018), 21520273 (2011), 20104584 (2010)), as well as in unaffected individuals in a breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA2)). In addition, this variant is reported to be located in a region of the BRCA2 gene that is tolerant to missense changes (PMID: 31911673 (2020)). The frequency of this variant in the general population, 0.0002 (4/19950 chromosomes, http://gnomad.broadinstitute.org), is uninformative in 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. -

Hereditary cancer-predisposing syndrome

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 03, 2017	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	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). -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 21, 2017	- -

Breast-ovarian cancer, familial, susceptibility to, 2

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 13, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Sep 12, 2012	- -

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.Ser1832Tyr variant was identified in 1 of 4206 proband chromosomes (frequency: 0.0002) from individuals or families with breast cancer (Borg 2010). The variant was also identified in dbSNP (ID: rs138489917) as With Uncertain significance allele, ClinVar (classified as likely benign by Ambry Genetics, Invitae, SCRP; classified as uncertain significance by GeneDx), Genesight-COGR (classified as unknown significance), UMD-LSDB (2X uncertain significance), databases. The variant was not identified in Cosmic, MutDB, LOVD 3.0, BIC Database, ARUP Laboratories, Zhejiang Colon Cancer Database, databases. The variant was identified in control databases in 5 of 276638 chromosomes at a frequency of 0.00002 increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The p.Ser1832 residue is 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. The variant is located with the Breast cancer type 2 susceptibility protein functional domain increasing the likelihood that it may have clinical significance. In addition, in an in silico study of 2103 women with unilateral and contralateral breast cancer the variant was found in patient with unilateral breast cancer and determined unclassified (Borg 2010). 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. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Apr 17, 2024

Variant summary: BRCA2 c.5495C>A (p.Ser1832Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 250668 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5495C>A has been reported in the literature in individuals affected with breast cancer (e.g. Borg_2010, Momozawa_2018). These reports however, do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. A study using multifactorial probability likelihood analysis reported this variant as strong in favour of a benign outcome (Parsons_2019). At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (BRCA1 c.5096G>A, p.Arg1699Gln), 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: 20104584, 21520273, 30287823, 28222693, 31131967). ClinVar contains an entry for this variant (Variation ID: 91415). Based on the evidence outlined above, the variant was classified as likely benign. -

Hereditary breast ovarian cancer syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.092

BayesDel_noAF

Benign

-0.11

CADD

Benign

DANN

Uncertain

0.98

Eigen

Benign

-0.10

Eigen_PC

Benign

-0.27

FATHMM_MKL

Benign

0.19

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.34

T;T

MetaSVM

Benign

-0.43

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.31

PROVEAN

Pathogenic

-4.7

D;D

REVEL

Uncertain

0.41

Sift

Benign

0.098

T;T

Sift4G

Benign

0.090

T;T

Vest4

0.38

MutPred

0.28

Loss of disorder (P = 0.0027);Loss of disorder (P = 0.0027);

MVP

0.93

MPC

0.050

ClinPred

0.61

GERP RS

3.9

gMVP

0.32

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