rs80359282

Positions:

• chr13-32332836-CA-C
• chr13-32332836-CA-CAA

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.1362delA​(p.Lys454fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,068 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. K454K) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:9
• Conservation: PhyloP100: 0.108

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 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 13-32332836-CA-C is Pathogenic according to our data. Variant chr13-32332836-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 51109.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32332836-CA-C is described in Lovd as [Pathogenic]. Variant chr13-32332836-CA-C is described in Lovd as [Pathogenic]. Variant chr13-32332836-CA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.1362delA	p.Lys454fs	frameshift_variant	10/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.1362delA	p.Lys454fs	frameshift_variant	10/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.993delA	p.Lys331fs	frameshift_variant	10/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.1362delA		non_coding_transcript_exon_variant	9/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459068 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 725676

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: reviewed by expert panel

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	May 11, 2022	The BRCA2 c.1362del variant is classified as Pathogenic (PVS1, PS4_Supporting, PM2) This BRCA2 c.1362del variant is located in exon 10/27 and is predicted to cause a shift in the reading frame at codon 454. BRCA2:c.1362del has been reported in an individual with breast cancer (Fackenthal et al., 2012 PMID:22034289). (PS4_Supporting). This variant is absent from population databases (PM2). BRCA2:c.1362del (rs397507582) is absent from population databases and is not on record in FLOSSIES. BRCA2:c.1362del has been reported in an individual with breast cancer (Fackenthal et al., 2012 PMID:22034289). The variant has been reported in dbSNP (rs80359282) and has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 51109). It has not been reported in HGMD. -
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, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 20, 2016	- -
Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Oct 18, 2016	Variant allele predicted to encode a truncated non-functional protein. -

Hereditary breast ovarian cancer syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 17, 2023	ClinVar contains an entry for this variant (Variation ID: 51109). This variant is also known as 1590delA. This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 22034289). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys454Asnfs*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). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 28, 2019	The p.Lys454AsnfsX6 variant in BRCA2 has been reported in 1 individual with breast cancer (Fackenthal 2012). Additionally, it was classified as Pathogenic on Oct. 18, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID: 51109). This variant was absent from large population studies. The p.Lys454AsnfsX6 variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 454 and leads to a premature termination codon 6 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the BRCA2 gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer syndrome (HBOC). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2. -
Pathogenic, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Jan 31, 2014	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 27, 2020

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; Not observed in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 1590delA; Observed in individuals with BRCA2-related cancers (Fackenthal 2012); This variant is associated with the following publications: (PMID: 22034289, 31060517) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 22, 2023

The c.1362delA pathogenic mutation, located in coding exon 9 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 1362, causing a translational frameshift with a predicted alternate stop codon (p.K454Nfs*6). This mutation has been previously reported in a Nigerian patient who was diagnosed with breast cancer at age 35 (Fackenthal JD et al. Int. J. Cancer. 2012 Sep;131:1114-23). 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. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs80359282; hg19: chr13-32906973;