NM_000059.4:c.8415_8416delAT

Variant names:

• chr13-32370483-TTA-T
• rs397507402
• NM_000059.4:c.8415_8416delAT

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000059.4(BRCA2):​c.8415_8416delAT​(p.Leu2805PhefsTer6) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,584 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. L2805L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:1 O:1
• Conservation: PhyloP100: 7.95
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• breast-ovarian cancer, familial, susceptibility to, 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• Fanconi anemia complementation group D1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
• pancreatic cancer, susceptibility to, 2

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary breast ovarian cancer syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• medulloblastoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 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 13-32370483-TTA-T is Pathogenic according to our data. Variant chr13-32370483-TTA-T is described in CliVar as Pathogenic. Clinvar id is 52579.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32370483-TTA-T is described in CliVar as Pathogenic. Clinvar id is 52579.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32370483-TTA-T is described in CliVar as Pathogenic. Clinvar id is 52579.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32370483-TTA-T is described in CliVar as Pathogenic. Clinvar id is 52579.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32370483-TTA-T is described in CliVar as Pathogenic. Clinvar id is 52579.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32370483-TTA-T is described in CliVar as Pathogenic. Clinvar id is 52579.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32370483-TTA-T is described in CliVar as Pathogenic. Clinvar id is 52579.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32370483-TTA-T is described in CliVar as Pathogenic. Clinvar id is 52579.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32370483-TTA-T is described in CliVar as Pathogenic. Clinvar id is 52579.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32370483-TTA-T is described in CliVar as Pathogenic. Clinvar id is 52579.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32370483-TTA-T is described in CliVar as Pathogenic. Clinvar id is 52579.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32370483-TTA-T is described in CliVar as Pathogenic. Clinvar id is 52579.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32370483-TTA-T is described in CliVar as Pathogenic. Clinvar id is 52579.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.8415_8416delAT	p.Leu2805PhefsTer6	frameshift_variant	Exon 19 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.8415_8416delAT	p.Leu2805PhefsTer6	frameshift_variant	Exon 19 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.8046_8047delAT	p.Leu2682PhefsTer6	frameshift_variant	Exon 19 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*473_*474delAT		non_coding_transcript_exon_variant	Exon 18 of 26	2		ENSP00000506251.1
BRCA2	ENST00000614259.2	n.*473_*474delAT		3_prime_UTR_variant	Exon 18 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461584 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 727126

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000299 AC: 1 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111744

Other (OTH) AF: 0.00 AC: 0 AN: 60388

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

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

Dec 15, 2017

Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

Variant allele predicted to encode a truncated non-functional protein. -

Familial cancer of breast Other:1

-

ClinVar Staff, National Center for Biotechnology Information (NCBI)

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.0
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs397507402; hg19: chr13-32944620;