rs55996097

Positions:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_000059.4(BRCA2):c.5635G>A(p.Glu1879Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000893 in 1,612,052 control chromosomes in the GnomAD database, including 1 homozygotes. 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).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000090 ( 1 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:21

Conservation

PhyloP100: 0.477

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 -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.060434014).

BP6

Variant 13-32339990-G-A is Benign according to our data. Variant chr13-32339990-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 51895.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=9, Benign=5, Uncertain_significance=1}. Variant chr13-32339990-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4 linkuse as main transcript	c.5635G>A	p.Glu1879Lys	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.5635G>A	p.Glu1879Lys	missense_variant	11/27	5	NM_000059.4	ENSP00000369497	A2

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.000132

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000133

AC:

AN:

248816

Hom.:

AF XY:

0.000171

AC XY:

AN XY:

134454

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000168

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000239

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000904

AC:

132

AN:

1459830

Hom.:

Cov.:

AF XY:

0.000102

AC XY:

AN XY:

726032

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000675

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000152

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000963

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000124

Hom.:

Bravo

AF:

0.0000642

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000214

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:21

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:1Benign:7

Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The BRCA2 p.Glu1879Lys variant was identified in 3 of 4882 proband chromosomes (frequency: 0.0006) from Malaysian and American individuals or families with breast or endometrial cancer (Thirthagiri 2008, Pennington 2012, Borg 2010). The variant was also identified in dbSNP (ID: rs55996097) â€šÃ„ÃºWith Pathogenic, other alleleâ€šÃ„Ã¹, ClinVar (conflicting interpretations of pathogenicity: classified as benign by Invitae and SCRP; classified as likely benign by Ambry Genetics, GeneDx, Illumina Clinical Services Laboratory, and two other clinical laboratories; and classified as uncertain significance by BIC, Integrated Genetics/Laboratory Corporation of America, CHEO and Quest Diagnostics Nichols Institute San Juan Capistrano), GeneInsight-COGR (1x), LOVD 3.0 (1x), UMD-LSDB (classified as 3-UV, co-occurring with the pathogenic variant BRCA2 c.8643dup, p.Ile2822Tyrfs*23) and BIC Database (10x, clinical importance unknown, classification pending). The variant was not identified in Cosmic, MutDB, ARUP Laboratories, or the Zhejiang University Database. The variant was identified in control databases in 35 of 274724 chromosomes (1 homozygous) at a frequency of 0.0001, 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: European Non-Finnish in 28 of 125750 chromosomes (freq: 0.0002), and South Asian in 7 (1 homozygous) of 29948 chromosomes (freq: 0.0002), while it was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, or Finnish populations. The p.Glu1879 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. 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. -
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. -
Benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Aug 24, 2009	- -
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	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)+BP1(Strong)+BP5(Moderate) 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) -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -

not provided

Uncertain:1Benign:4

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 19, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 06, 2017	The p.Glu1879Lys variant has been reported in individuals with breast and/or ovarian cancer; however, inheritance and specific clinical information were not reported (Borg 2010, Pennington 2012, and Thirthagiri 2008). The p.Glu1879Lys variant is listed in the Genome Aggregation Database (gnomAD) browser with an allele frequency of 0.023% in the South Asian population (identified in 7 out of 29,948 chromosomes; 1 homozygote), and is classified as likely benign/benign in ClinVar (Variant ID: 51895). The glutamic acid at codon 1,879 is moderately conserved considering 12 species (Alamut software v2.9.0), and it is a lysine in dogs, suggesting that this change may be evolutionary tolerated. Computational analyses predict that this variant does not affect the BRCA2 protein structure/function (GV/GD: C0, SIFT: tolerated, PolyPhen2: benign, MutationTaster: polymorphism). Based on the available evidence, the p.Glu1879Lys variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 10, 2020	This variant is associated with the following publications: (PMID: 32426482, 27062684, 28222693, 28263838, 18092194, 24504028, 26689913, 23555315, 20104584, 18627636, 22811390, 16847550, 16760289) -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Hereditary cancer-predisposing syndrome

Benign:4

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	May 06, 2021	- -
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	Ambry Genetics	Dec 28, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 08, 2016	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 27, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 16, 2020	Variant summary: BRCA2 c.5635G>A (p.Glu1879Lys) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 248816 control chromosomes, predominantly at a frequency of 0.00024 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer allowing no conclusion about variant significance. c.5635G>A has been reported in the literature in sequencing studies of individuals affected with Hereditary Breast and Ovarian Cancer, contralateral breast cancer, and other cancerous settings ((example, Borg_2010, Capalbo_2006, Capanu_2011, Cunningham_2014, Giannini_2006, Haiman_2013, Pennington_2013, Seymour_2008, Thirthagiri_2008, Azzolini_2016, Lai_2017, Zuntini_2018). The variant was reported as not co-segregating with disease in at-least one of these reports (Zuntini_2018). Therefore, these report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variants in the BRCA2 and BRCA1 genes have been reported in the UMD and the BIC databases respectively in addition to another co-occurrence in the MSH6 gene tested at our laboratory (BRCA2 c.8463dup, p.Ile2822fs; BRCA1 c.5263_5264insC, p.Ser1755?fs, MSH6 c.3733_3739dupTTTTCAA , p.Thr1247fsX30), providing additional supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Some of these submitters cite overlapping evidence utilized in the context of this evaluation. All laboratories classified the variant as benign (n=2)/likely benign (n=6). Based on the evidence outlined above, the variant was re-classified from likely benign to benign. -

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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

BRCA2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 04, 2019

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). -

Hereditary breast ovarian cancer syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.23

CADD

Benign

5.7

DANN

Uncertain

0.97

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.13

M_CAP

Benign

0.028

MetaRNN

Benign

0.060

T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.28

PROVEAN

Uncertain

-2.5

D;D

REVEL

Uncertain

0.34

Sift

Benign

0.41

T;T

Sift4G

Benign

0.46

T;T

Vest4

0.31

MVP

0.83

MPC

0.023

ClinPred

0.023

GERP RS

3.0

gMVP

0.23

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