chr13-32398608-C-GAATTATATCT

Position:

• chr13-32398608-C-GAATTATATCT

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PVS1_Moderate PM2 BP6

The NM_000059.4(BRCA2):​c.10095delinsGAATTATATCT​(p.Ser3366AsnfsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V3365V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3 B:16
• Conservation: PhyloP100: 0.00700

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0158 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 13-32398608-C-GAATTATATCT is Benign according to our data. Variant chr13-32398608-C-GAATTATATCT is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 125926.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=2, Benign=4}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.10095delinsGAATTATATCT	p.Ser3366AsnfsTer4	frameshift_variant	27/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.10095delinsGAATTATATCT	p.Ser3366AsnfsTer4	frameshift_variant	27/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3 Benign:16

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:6

Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The BRCA2 p.Ser3366Asnfs*4 variant was identified in 19 of 9215 proband chromosomes (frequency: 0.002) from individuals or families with pancreatic and hereditary breast and ovarian cancer and identified in 1 of 490 chromosomes (frequency: 0.002) from healthy individuals (Borg 2010, Hahn 2003, Koczowska 2016, Wojcik 2016, Ratajska 2008, Balabas 2010, Houdayer 2012, Meindl 2002, Kim 2005, Thomassen 2008, Machakova 2008, Stegel 2011). The variant was identified in ClinVar (classified as benign by Ambry Genetics, BIC, Integrated Genetics, and 2 other submitters, uncertain significance by PreventionGenetics, Western University and 2 other submitters and likely benign by Invitae, Pathway Genomics and 1 other submitter), LOVD 3.0 (observed 1x), UMD-LSDB (observed 25x) .The variant was not identified in dbSNP, Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). In UMD-LSDB, the variant was observed in samples with co-occurring pathogenic BRCA1 variants (c.2959A>T p.Lys987*, c.1171G>T p.Glu391*). Additionally, the variant had no observed effect on both BRCA2 mRNA expression and in vitro splicing (Stordal 2013, Houdayer 2012). The c.10095delinsGAATTATATCT variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 3366 and leads to a premature stop codon at position 3369. This alteration is then predicted to result in a truncated or absent protein. Truncations downstream of the Lys3326 residue are predicted to retain the biological functions of BRCA2 and are not believed to be pathogenic, however this has not been tested experimentally (Borg 2010, Negura 2012). 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. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 30113427, 22505045, 12569143) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 11, 2022	PM2 -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 03, 2016	Variant summary: The c. 10095delinsGAATTATATCT (p.Ser3366Asnfs) variant in BRCA2 has been reported in the literature to be found in prostate, breast and ovarian cancer patients, without strong evidence for causality. The variant was identified in at least 1 healthy individual from the literature, but not amongst the 1000G, ExAC or and ESP cohort. Multiple reputable clinical labs/databases have classified the variant as benign/likely benign. The variant is located 51 amino acids from the end of the protein and 40 amino acids downstream from the c.9976A>T (p.Lys3326X) variant, which was proven to be non pathogenic and It is generally accepted that truncations downstream of Lys3326 are non-pathogenic. Additionally, the variant was found to co-occur with several pathogenic BRCA1/2 variants via UMD: BRCA2 c.17_18delAA (p.Lys6Argfs), BRCA1 c.2959A>T (p.Lys987X), BRCA1 c.1171G>T (p.Glu391X). The variant was also shown to have no effect on splicing (Houdayer_2012). The variant of interest shows strong evidence for neutrality, and has been classified as a benign variant. -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 17, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	BRCA2: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 09, 2023	- -

Breast-ovarian cancer, familial, susceptibility to, 2 Benign:4

Likely benign, no assertion criteria provided	literature only	Pathway Genomics	Jul 24, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Michigan Medical Genetics Laboratories, University of Michigan	Apr 21, 2016	- -
Benign, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Dec 17, 2010	- -
Likely benign, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -

Hereditary breast ovarian cancer syndrome Uncertain:2

Uncertain significance, no assertion criteria provided	research	Dr. Peter K. Rogan Lab, Western University	Dec 22, 2015	Sequenced patient with familial breast cancer -
Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Feb 02, 2016	Interpretation was last updated within 1 year from 2/2/2016 11:04 AM -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 06, 2020	- -
Benign, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Jan 31, 2014	- -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 19, 2014	This alteration is classified as 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	Sep 22, 2015	- -

Breast carcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences

Sep 11, 2021

- -

Breast and/or ovarian cancer Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Dec 05, 2022

- -

BRCA2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 11, 2023

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). -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs276174803; hg19: chr13-32972745; COSMIC: COSV66338166; COSMIC: COSV66338166;