rs397507322

Positions:

• chr13-32338411-TGAAAC-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000059.4(BRCA2):​c.4058_4062del​(p.Glu1353GlyfsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,451,810 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:11
• Conservation: PhyloP100: 2.20

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-32338411-TGAAAC-T is Pathogenic according to our data. Variant chr13-32338411-TGAAAC-T is described in ClinVar as [Pathogenic]. Clinvar id is 37875.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32338411-TGAAAC-T is described in Lovd as [Pathogenic]. Variant chr13-32338411-TGAAAC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.4058_4062del	p.Glu1353GlyfsTer6	frameshift_variant	11/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.4058_4062del	p.Glu1353GlyfsTer6	frameshift_variant	11/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1451810 Hom.: 0 AF XY: 0.00000139 AC XY: 1 AN XY: 721308

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: reviewed by expert panel

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter	clinical testing	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Oct 23, 2013	- -
Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Sep 08, 2016	Variant allele predicted to encode a truncated non-functional protein. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Nov 08, 2016	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 06, 2023	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 4286_4290delAAACG; This variant is associated with the following publications: (PMID: 25186627, 21318380, 29446198, 30720243) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 10, 2021	This frameshift variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been reported in individuals affected with breast cancer in the published literature (PMID: 21318380 (2011), 25186627 (2015), 29446198 (2018)). This variant has not been reported in large, multi-ethnic general populations. Based on the available information, this variant is classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 27, 2022	This variant deletes 5 nucleotides in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in one individual affected with breast cancer, over the age of 50 at the time of diagnosis, with a family history of breast cancer (PMID: 25186627) and has been identified in 1 family among the CIMBA participants (PMID: 29446198). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 26, 2022	The c.4058_4062delAAACG pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 5 nucleotides at nucleotide positions 4058 to 4062, causing a translational frameshift with a predicted alternate stop codon (p.E1353Gfs*6). This variant was observed in an individual with early onset-breast cancer amongst a cohort of 1781 non-Ashkenazi Jewish individuals undergoing BRCA1/2 gene testing based on a personal history of breast cancer (Tung N et al. Cancer, 2015 Jan;121:25-33). This alteration was also identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Hereditary breast ovarian cancer syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2024	This sequence change creates a premature translational stop signal (p.Glu1353Glyfs*6) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant is present in population databases (rs397507322, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 21318380). This variant is also known as c.4057_4061del5 and 4286del5. ClinVar contains an entry for this variant (Variation ID: 37875). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 13, 2022	Variant summary: BRCA2 c.4058_4062delAAACG (p.Glu1353GlyfsX6) 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. Multiple truncations downstream of this position have been classified as pathogenic by our laboratory (example c.4092_4093delAT [p.Ile1364fsX3], c.4111C>T [p.Gln1371X], and c.4133_4136delCTCA [p.Thr1378fsX9]). The variant was absent in 241134 control chromosomes (gnomAD). c.4058_4062delAAACG has been reported in the literature in individuals affected with and a family history of breast and/or ovarian cancers (example Tung_2014, Rebbeck_2018). These data indicate that the variant is likely with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical-significance assessments for this variant have been submitted to ClinVar after 2014. Seven submitters classified the variant as pathogenic and one as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jan 23, 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: rs397507322; hg19: chr13-32912548;