rs56242644

Positions:

• chr13-32325102-A-G
• chr13-32325102-A-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001406722.1(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 NM_001406722.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:1
• Conservation: PhyloP100: 2.06

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2310085).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.343A>G	p.Lys115Glu	missense_variant	4/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000530893	c.-27A>G		5_prime_UTR_premature_start_codon_gain_variant	4/27	1		ENSP00000499438.2
BRCA2	ENST00000380152.8	c.343A>G	p.Lys115Glu	missense_variant	4/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893	c.-27A>G		5_prime_UTR_variant	4/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.343A>G		non_coding_transcript_exon_variant	3/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 251004 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135718

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000221 AC: 32 AN: 1449850 Hom.: 0 Cov.: 29 AF XY: 0.0000208 AC XY: 15 AN XY: 722074

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.0000254

Gnomad4 OTH exome AF: 0.0000500

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000386 Hom.: 0

Bravo AF: 0.0000113

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 21, 2023	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 a patient with high-grade serous ovarian cancer (Marchetti C et al, 2018 Nov;25:3701-3708). This alteration has been reported in a Chinese patient diagnosed with esophageal squamous cell carcinoma (Hu N et al. Cancer Detect. Prev. 2003;27(2):132-8). In a study of whole-exome sequencing in patients with features of Cowden syndrome (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS) and negative PTEN testing, this alteration was identified in 0/87 patients with CS or BRRS and 1/3476 patients from The Cancer Genome Atlas (TCGA) (Yehia L et al, 2018 04;14:e1007352). 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Dec 06, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 29, 2016	- -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 14, 2022	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 30, 2016	- -

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	May 26, 2016	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Nov 25, 2004	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 20, 2018

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 21, 2023

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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	17
DANN	Uncertain	1.0
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.49	N
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.23	T;T
MetaSVM	Benign	-0.92	T
PrimateAI	Benign	0.36	T
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	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.22

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

LitVar

Other links and lift over

dbSNP: rs56242644; hg19: chr13-32899239;