Variant 13-32332694-GCCC-ACCG details in Genebe, Genetics Data Aggregator

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:

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4 linkuse as main transcript	c.1216_1219delinsACCG	p.Ala406_Gln407delinsThrGlu	missense_variant	10/27	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.1216_1219delinsACCG	p.Ala406_Gln407delinsThrGlu	missense_variant	10/27	5	NM_000059.4	ENSP00000369497	A2

Frequencies

GnomAD3 genomes

Cov.:

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 30, 2021	The c.1216_1219delGCCCinsACCG variant (also known as p.A406_Q407delinsTE), located in coding exon 9 of the BRCA2 gene, results from an in-frame deletion of GCCC and insertion of ACCG at nucleotide positions 1216 to 1219. This results in the substitution of alanine and glutamine residues for a threonine and glutamate at codon 406 and 407. This amino acid region is not well conserved in available vertebrate species. In addition, this alteration is predicted to be neutral by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
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). -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Sep 02, 2022

Variant summary: BRCA2 c.1216_1219delinsACCG (p.Ala406_Gln407delinsThrGlu) results in an in-frame deletion-insertion that that replaces two adjacent amino acids (alanine and glutamine) at codons 406-407 with two different amino acids (threonine and glutamic acid). This variant is reported as two separate single-nucleotide changes (i.e. c.1216G>A (p.Ala406Thr) and c.1219C>G (p. Gln407Glu)) in the gnomAD database, however read data indicate that these variants were found in cis, therefore the variant allele is likely found at a frequency of 1.1e-05 in ~281500 control chromosomes. The variant was absent in 281524 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The c.1216G>A and c.1219C>G variants have been reported together in multiple cohorts of individuals who had personal and/or family history of breast/ovarian cancer (Caux-Moncoutier_2011, Alsop_2012, Dorling_2021). However, these reports do not specify whether the two variants were observed together in the same individuals or separately in different individuals. A recent study reported the two component variants (c.1216G>A and c.1219C>G) in an endometrioid adenocarcinoma patient (Akaev_2021), however the phase of these variants was not specified. On the other hand, a co-occurrence of the c.1216G>A and c.1219C>G variants (phase not specified) with another pathogenic variant (BRCA2 c.3599_3600del (p.Cys1200X); in LOVD) has also been reported in a breast cancer patient, providing supporting evidence for a benign role. Furthermore, one study reported the variant c.1216_1219delinsACCG in an ovarian cancer patient (Hauke_2020). To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all of them classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The BRCA2 p.Ala406_Gln407delinsThrGlu variant was not identified in the literature nor was it identified in the LOVD 3.0 or UMD-LSDB databases. The variant was identified in dbSNP (ID: rs886037742) as "With Uncertain significance allele" and ClinVar (classified as uncertain significance by GeneDx and Invitae). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). This variant is an in-frame deletion-insertion resulting in the removal of an Alanine (Ala) residue at codon 406 and Glutamine (Gln) residue at codon 407 and insertion of Threonine (Thr) and Glutamate (Glu); the impact of this alteration on BRCA2 protein function is not known. In silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a greater than 10% difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 11, 2023

In-frame deletion and insertion of four amino acids in a non-repeat region; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this variant does not alter protein structure/function; Also known as 1444_1447delGCCCinsACCG; This variant is associated with the following publications: (PMID: 33808557, 33273034, 33471991, 22711857, 21120943) -

Hereditary breast ovarian cancer syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 09, 2019

This is a complex sequence change that replaces alanine and glutamine with threonine and glutamic acid at codons 406-407 of the BRCA2 protein (p.Ala406_Gln407delinsThrGlu). This variant is reported as two separate single-nucleotide changes in population databases (c.1216G>A, ExAC 0.001% and c.1219C>G, ExAC 0.001%). However, in the read data for the two individuals displayed in the ExAC browser, these two variants are in cis. This recapitulates the variant observed here (c.1216_1219delinsACCG) and indicates that this variant is very likely present in the population databases at 0.001%. The p.Ala406Thr and p.Gln407Glu variants have been reported in individuals affected with hereditary breast and/or ovarian cancer (PMID: 21120943, 22711857) and also co-occurred with a BRCA2 pathogenic allele in an individual with breast cancer in the Leiden Open-source Variation Database (PMID: 21520333). However, these publications do not specify whether the two variants were observed together in a single individual or separately in different individuals. ClinVar contains an entry for this variant (Variation ID: 182308). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the disrupted amino acids is currently unknown. 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

Splicing

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.

13-32332694-GCCC-ACCG

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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