rs80359251

Positions:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_000059.4(BRCA2):c.9925G>A(p.Glu3309Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000446 in 1,614,014 control chromosomes in the GnomAD database, with no homozygous occurrence. 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E3309V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:10O:1

Conservation

PhyloP100: 0.810

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 -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07175356).

BP6

Variant 13-32398438-G-A is Benign according to our data. Variant chr13-32398438-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 52918.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=9, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4 linkuse as main transcript	c.9925G>A	p.Glu3309Lys	missense_variant	27/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8 linkuse as main transcript	c.9925G>A	p.Glu3309Lys	missense_variant	27/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes

AF:

0.000243

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000845

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000557

AC:

AN:

251252

Hom.:

AF XY:

0.0000663

AC XY:

AN XY:

135790

show subpopulations

Gnomad AFR exome

AF:

0.000677

Gnomad AMR exome

AF:

0.0000868

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000239

AC:

AN:

1461872

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.000687

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.000243

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.000845

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.000306

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:10Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 10, 2021	The p.Glu3309Lys variant in BRCA2 has been reported in one individual with breast cancer and 2 individuals with other cancers (Pal 2015 PMID: 26287763, Parry 2017 PMID: 28843361, Mandelker 2017 PMID: 28873162). It has also been identified in 0.08% (20/24958) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of this variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: BP4. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	BRCA2: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 27, 2020	This variant is associated with the following publications: (PMID: 25451944, 24728327, 26689913, 28873162, 26295337, 26287763) -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 23, 2022	- -

Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:2Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Dec 23, 2003	- -
Benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Dec 17, 2009	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Hereditary cancer-predisposing syndrome

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 07, 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. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 16, 2015	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jul 19, 2021	- -

not specified

Benign:1Other:1

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 24, 2024	Variant summary: BRCA2 c.9925G>A (p.Glu3309Lys) 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 8.1e-05 in 282626 control chromosomes, predominantly at a frequency of 0.0008 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer phenotype (0.00075), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. The variant, c.9925G>A, has been reported in the literature in individuals affected with cancer, including breast cancer and lung adenocarcinoma (Pal_2015, Lu_2015, Mandelker_2017, Parry_2017, Ren_2021). These reports however, do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At-least one co-occurrence with a pathogenic variant has been observed at our laboratory (BRCA2 c.7110dupA , p.Ser2371fsX21; internal testing), providing supporting evidence for a benign role. c.9925G>A has been reported in the FLOSSIES database in 9 women older than age 70 years who have never had cancer, providing further supporting evidence for a benign role. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Ghosh_2015). The following publications have been ascertained in the context of this evaluation (PMID: 24728327, 25451944, 26689913, 28873162, 26287763, 28843361, 34196900). ClinVar contains an entry for this variant (Variation ID: 52918). Based on the evidence outlined above, the variant was classified as likely benign. -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

BRCA2-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 16, 2020

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Uncertain

1.0

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.063

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.072

T;T

MetaSVM

Benign

-0.89

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.80

N;N

REVEL

Benign

0.12

Sift

Benign

0.32

T;T

Sift4G

Benign

0.75

T;T

Vest4

0.18

MVP

0.84

MPC

0.17

ClinPred

0.073

GERP RS

2.5

gMVP

0.24

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