rs1064792995

chr13-32398607-T-TGAATTATATC

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 4P and 8B. PVS1_Moderate PM2 BP6_Very_Strong

The NM_000059.4(BRCA2):c.10094_10095insGAATTATATC(p.Ser3366AsnfsTer5) 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V3365VNYI?) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:2 B:7
• 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 Likely_benign. Variant got -4 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 0.0159 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 13-32398607-T-TGAATTATATC is Benign according to our data. Variant chr13-32398607-T-TGAATTATATC is described in ClinVar as [Likely_benign]. Clinvar id is 415704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.10094_10095insGAATTATATC	p.Ser3366AsnfsTer5	frameshift_variant	27/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.10094_10095insGAATTATATC	p.Ser3366AsnfsTer5	frameshift_variant	27/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:2 Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2019	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 19, 2020	The p.Ser3366AsnfsX5 variant in BRCA2 has been identified in individuals with hereditary breast and ovarian cancer (Schenkel 2016 PMID: 27376475, Johnston 2015 PMID: 26046366 ); however, it is not expected to be clinically significant because it has been identified in >30/150 normal controls from the Czech Republic (Machackova 2019 PMID: 31409081) and has been identified in an individual with a pathogenic BRCA1 variant (Koczkowska 2016 PMID: 27167707). In addition, a smiliar change at this position (c.10095delinsGAATTATATCT (p.Ser3366AsnfsX4)) is also catagorized as likely benign. Although this variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 3366 and leads to a premature termination codon 5 amino acids downstream, this termination codon occurs within the last exon and is, therefore, likely to escape nonsense mediated decay (NMD) and result in a truncated protein. ACMG/AMP codes applied: BS1; BP5. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 27, 2022	Variant summary: BRCA2 c.10094_10095ins10 (c.10094_10095insGAATTATATC, p.Ser3366AsnfsX5) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. However, this variant is located only 51 amino acids from the end of the protein, and 40 amino acids downstream of a well-known polymorphism c.9976A>T (p.Lys3326X), suggesting that it may be a neutral polymorphism. In general, because BRCA2 c.9976A>T has been proven to be non-pathogenic, it is commonly accepted that the region of the BRCA2 gene beyond codon 3326 is not crucial for proper function. The variant was absent in 251160 control chromosomes in gnomAD, but has been reported in healthy controls including 8 European American women older than age 70 years who have never had cancer (FLOSSIES database). c.10094_10095ins10 has been reported in the literature in individuals affected with prostate cancer (Na_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign. Another frameshift variant affecting the same codon (c. 10095delinsGAATTATATCT; p.Ser3366AsnfsX4) has been classified as benign by our laboratory. Based on the evidence outlined above, the variant was classified as likely benign. -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 19, 2017	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	Jan 10, 2018	- -

Breast-ovarian cancer, familial, susceptibility to, 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 17, 2015

- -

Hereditary breast ovarian cancer syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

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: rs1064792995; hg19: chr13-32972744;