rs56242644

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The ENST00000530893.7(BRCA2):c.-27A>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000221 in 1,449,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

BRCA2
ENST00000530893.7 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:1

Conservation

PhyloP100: 2.06

Publications

13 publications found

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 Gene-Disease associations (from GenCC):

breast-ovarian cancer, familial, susceptibility to, 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
Fanconi anemia complementation group D1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
pancreatic cancer, susceptibility to, 2
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
sarcoma
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
hereditary breast ovarian cancer syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Fanconi anemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
medulloblastoma
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

BRCA2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.2310085).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4 link	c.343A>G	p.Lys115Glu	missense_variant	Exon 4 of 27	ENST00000380152.8	NP_000050.3	P51587

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
BRCA2	ENST00000530893.7 link	c.-27A>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 4 of 27	1		ENSP00000499438.2	A0A590UJI7
BRCA2	ENST00000380152.8 link	c.343A>G	p.Lys115Glu	missense_variant	Exon 4 of 27	5	NM_000059.4	ENSP00000369497.3	P51587
BRCA2	ENST00000614259.2 link	n.343A>G		non_coding_transcript_exon_variant	Exon 3 of 26	2		ENSP00000506251.1	A0A7P0TAP7
BRCA2	ENST00000530893.7 link	c.-27A>G		5_prime_UTR_variant	Exon 4 of 27	1		ENSP00000499438.2	A0A590UJI7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000797

AC:

AN:

251004

AF XY:

0.00000737

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000221

AC:

AN:

1449850

Hom.:

Cov.:

AF XY:

0.0000208

AC XY:

AN XY:

722074

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33202

American (AMR)

AF:

0.00

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26078

East Asian (EAS)

AF:

0.00

AC:

AN:

39600

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86002

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53248

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.0000254

AC:

AN:

1101232

Other (OTH)

AF:

0.0000500

AC:

AN:

60024

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000266

Hom.:

Bravo

AF:

0.0000113

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:1

May 29, 2016

Color Diagnostics, LLC DBA Color Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 23, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.K115E variant (also known as c.343A>G), located in coding exon 3 of the BRCA2 gene, results from an A to G substitution at nucleotide position 343. The lysine at codon 115 is replaced by glutamic acid, an amino acid with similar properties. This alteration was detected in an individual diagnosed with high-grade serous ovarian cancer (Marchetti C et al, 2018 Nov;25:3701-3708). This alteration was classified as likely benign based on a multifactorial analysis model of variant classification (Parsons MT et al, 2019 09;40:1557-1578). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Dec 06, 2021

Sema4, Sema4

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

- -

not specified

Uncertain:2

Feb 14, 2022

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: BRCA2 c.343A>G (p.Lys115Glu) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251004 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.343A>G has been reported in the literature in individuals affected with esophageal and ovarian cancer (Hu_2003, Marchetti_2018). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrence with one pathogenic variant has been reported (BRCA1 c.3869_3870delAA, p.Lys1290fsX4), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters have assessed the variant since 2014: five have classified the variant as of uncertain significance and one as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Sep 30, 2016

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:2

May 26, 2016

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Nov 25, 2004

Breast Cancer Information Core (BIC) (BRCA2)

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Uncertain:1

Nov 20, 2018

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is denoted BRCA2 c.343A>G at the cDNA level, p.Lys115Glu (K115E) at the protein level, and results in the change of a Lysine to a Glutamic Acid (AAA>GAA). Using alternate nomenclature, this variant would be defined as BRCA2 571A>G. This variant has been observed in an individual with ovarian cancer and in at least one other individual evaluated for cancer predisposition (Cheng 2017, Marchetti 2018). BRCA2 Lys115Glu was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Lys115Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -

Hereditary breast ovarian cancer syndrome

Uncertain:1

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 115 of the BRCA2 protein (p.Lys115Glu). This variant is present in population databases (rs56242644, gnomAD 0.002%). This missense change has been observed in individual(s) with esophageal cancer and/or ovarian cancer (PMID: 12670525, 30128899). ClinVar contains an entry for this variant (Variation ID: 51463). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.018

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

DANN

Uncertain

1.0

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.37

FATHMM_MKL

Benign

0.49

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.23

T;T

MetaSVM

Benign

-0.92

PhyloP100

2.1

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.91

N;N

REVEL

Benign

0.12

Sift

Uncertain

0.0070

D;D

Sift4G

Benign

0.093

T;T

Vest4

0.38

MVP

0.83

MPC

0.027

ClinPred

0.25

GERP RS

3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.22

Mutation Taster

=91/9

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over