rs80358968

Positions:

Variant summary

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

The NM_000059.4(BRCA2):c.7463G>A(p.Arg2488Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000198 in 1,461,716 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. R2488N) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:8

Conservation

PhyloP100: 5.84

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 chr13-32356454-AGA-AAT is described in Lovd as [Pathogenic].

BP6

Variant 13-32356455-G-A is Benign according to our data. Variant chr13-32356455-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 52336.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=6}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4 link	c.7463G>A	p.Arg2488Lys	missense_variant	15/27	ENST00000380152.8	NP_000050.3	P51587

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
BRCA2	ENST00000380152.8 link	c.7463G>A	p.Arg2488Lys	missense_variant	15/27	5	NM_000059.4	ENSP00000369497.3	P51587
BRCA2	ENST00000530893.7 link	c.7094G>A	p.Arg2365Lys	missense_variant	15/27	1		ENSP00000499438.2	A0A590UJI7
BRCA2	ENST00000614259.2 link	n.7463G>A		non_coding_transcript_exon_variant	14/26	2		ENSP00000506251.1	A0A7P0TAP7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251410

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135878

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000198

AC:

AN:

1461716

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

727180

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.0000252

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:4Benign:2

Likely benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Nov 29, 2012	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jan 22, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 07, 2015	- -

not provided

Uncertain:3Benign:2

Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	BRCA2, EXON15, c.7463G>A, p.Arg2488Lys, Heterozygous, Likely BenignrnThe BRCA2 p.Arg2488Lys variant was identified in 3 of 7698 proband chromosomes (frequency: 0.0004) from individuals or families with breast or ovarian cancer (Claes 2004, Caux-Moncoutier 2009). The variant was also identified in dbSNP (ID: rs80358968) as "With other allele", ClinVar (classified as likely benign by GeneDx, Ambry Genetics, SCRP, Color and Integrated Genetics/Laboratory Corporation of America; and as uncertain significance by four submitters), LOVD 3.0 (14x), and UMD-LSDB (1x as neutral). In the UMD-LSDB database, the variant was identified in multiple cases as co-occurring with pathogenic BRCA1 variants (c.1961dup, p.Tyr655ValfsX18; c.4183C>T, p.Gln1395X; c.IVS21+1G>T, r.spl?; c.4389C>A, p.Tyr1463X; and c.442_4357del, p.Glu149TyrfsX2) and a pathogenic BRCA2 variant (c.2745_2746delTT, p.Val917LysfsX18), increasing the likelihood that the p.Arg2488Lys variant does not have clinical significance. The variant was identified in control databases in 3 of 246180 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 1 of 33578 chromosomes (freq: 0.00003), European in 2 of 111652 chromosomes (freq: 0.00002), but not in the African, Other, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Arg2488 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The literature suggests a neutral classification of the variant. Caux-Moncoutier (2009) used an allelic imbalance assay to assess the putative impact of variants on splicing; no allelic imbalance was found for the variant, suggesting that it does not impact splicing. In addition, Claes (2004) found that the variant did not segregate with disease in one family. In addition, several in silico and in vitro studies using PAXgene, Minigene systems or functional evidence identified no change and classified the variant neutral with no effect on splicing (Houdayer 2012, Martelotto 2014). 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.rnAssessment Date: 2019/07/22rnReferences (PMIDs): 15026808, 19471317, 22505045, 25348012, 19043619 -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 15, 2024	The BRCA2 c.7463G>A (p.Arg2488Lys) variant has been reported in the published literature in individuals with hereditary breast and/or ovarian cancer (PMID: 15026808 (2004), 19471317 (2009), 35534704 (2022)). In multiple individuals, this variant has been seen where an alternate explanation for disease was also identified (URL: https://ncbi.nlm.nih.gov/clinvar/variation/52336, Accession: SCV000695069.2). Assessment of experimental evidence regarding the effect of this variant on protein function is inconclusive. Studies show that this variant does not affect BRCA2 mRNA splicing in vitro (PMID: 21673748 (2011), 22505045 (2012)). In addition, it was able to rescue BRCA2-deficient cells (PMID: 33293522 (2020)), however, further research is needed. The frequency of this variant in the general population, 0.000012 (3/251410 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. The variant is located in a region that is considered important for protein function and/or structure. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 26, 2020	This variant is associated with the following publications: (PMID: 25348012, 24817641, 19043619, 19471317, 20858050, 21673748, 22505045, 15026808, 27974384, 31102422, 31131967) -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -

Hereditary cancer-predisposing syndrome

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 31, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 23, 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. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Oct 19, 2020

Variant summary: BRCA2 c.7463G>A (p.Arg2488Lys) results in a conservative amino acid change located in the Breast cancer type 2 susceptibility protein, helical domain (IPR015252) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251410 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7463G>A has been reported in the literature in individuals affected with breast cancer, ovarian cancer and acute lymphoblastic leukemia (Claes_2004, Caux-Moncoutier_2009, de Smith_2019). Claes_2004 indicated the variant did not segregate with disease for one of the affected families. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. In addition, co-occurrences with other pathogenic variants have been reported (BRCA2 c.2745_2746delTT , p.Val917LysfsX18; BRCA1 c.1961dup, p.Tyr655ValfsX18; BRCA1 c.4183C>T, p.Gln1395X; BRCA1 c.IVS21+1G>T , c.5332+1G>T; BRCA1 c.4389C>A , p.Tyr1463X ; BRCA1 442_4357del , p.Glu149TyrfsX2, in UMD database), providing supporting evidence for a benign role. Although the variant is not located in a commonly known location to affect splicing (ie, within +/- 2 bp of an exon/intron junction), two publications found the variant to not affect splicing via functional studies (Caux-Moncoutier_2009, Houdayer_2012). Seven ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (3x) and likely benign (4x). 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

Nov 16, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.27

CADD

Uncertain

DANN

Uncertain

1.0

Eigen

Pathogenic

0.70

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.98

M_CAP

Uncertain

0.12

MetaRNN

Uncertain

0.74

D;D

MetaSVM

Uncertain

0.40

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.90

N;N

REVEL

Pathogenic

0.66

Sift

Benign

0.099

T;T

Sift4G

Benign

0.17

T;T

Vest4

0.77

MutPred

0.79

Loss of catalytic residue at R2488 (P = 0.0233);Loss of catalytic residue at R2488 (P = 0.0233);

MVP

0.94

MPC

0.17

ClinPred

0.94

GERP RS

5.5

gMVP

0.54

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