rs1555286303

Variant names:

• chr13-32356588-CTCTGCGTGTTCTCATAAACAGGTATGTGTTTGTCTACAATACTGATGGCTTTTATGACAGAGTGTAATTTTATTTCATTAACTAGTATCTACAAATGGCTTTGTTTAAAGAATGAACACATTAGTGCAGGAATGGATGAATGAAATCATCATATTTTCTAATTAGCCTGCAGTGGCAGCCTCTGGCCCCTTGCTAGGCCTGCCTCATCCTGCTAAAGTGATCTGTGCTTCCAAATTACTACTTCTTTTCCCCCTTCAAATCTTTCTTATTTTGTCATTGTAAA-C
• rs1555286303
• NM_000059.4:c.7598_7617+263del

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The ENST00000380152.8(BRCA2):​c.7597_7617+262del​(p.Ser2533_Gln2539del) variant causes a splice donor, conservative inframe deletion, splice region, intron 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 Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. S2533S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: BRCA2 ENST00000380152.8 splice_donor, conservative_inframe_deletion, splice_region, intron
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.54

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 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-32356588-CTCTGCGTGTTCTCATAAACAGGTATGTGTTTGTCTACAATACTGATGGCTTTTATGACAGAGTGTAATTTTATTTCATTAACTAGTATCTACAAATGGCTTTGTTTAAAGAATGAACACATTAGTGCAGGAATGGATGAATGAAATCATCATATTTTCTAATTAGCCTGCAGTGGCAGCCTCTGGCCCCTTGCTAGGCCTGCCTCATCCTGCTAAAGTGATCTGTGCTTCCAAATTACTACTTCTTTTCCCCCTTCAAATCTTTCTTATTTTGTCATTGTAAA-C is Pathogenic according to our data. Variant chr13-32356588-CTCTGCGTGTTCTCATAAACAGGTATGTGTTTGTCTACAATACTGATGGCTTTTATGACAGAGTGTAATTTTATTTCATTAACTAGTATCTACAAATGGCTTTGTTTAAAGAATGAACACATTAGTGCAGGAATGGATGAATGAAATCATCATATTTTCTAATTAGCCTGCAGTGGCAGCCTCTGGCCCCTTGCTAGGCCTGCCTCATCCTGCTAAAGTGATCTGTGCTTCCAAATTACTACTTCTTTTCCCCCTTCAAATCTTTCTTATTTTGTCATTGTAAA-C is described in ClinVar as [Pathogenic]. Clinvar id is 254094.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.7598_7617+263del	p.Ala2534TyrfsTer20	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 15 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.7597_7617+262del	p.Ser2533_Gln2539del	splice_donor_variant, conservative_inframe_deletion, splice_region_variant, intron_variant	Exon 15 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.7228_7248+262del	p.Ser2410_Gln2416del	splice_donor_variant, conservative_inframe_deletion, splice_region_variant, intron_variant	Exon 15 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.7597_7617+262del		splice_donor_variant, splice_region_variant, intron_variant, non_coding_transcript_exon_variant	Exon 14 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary breast ovarian cancer syndrome Pathogenic:1

May 25, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change deletes 283 nucleotides from exon 15 of the BRCA2 mRNA (c.7598_7617+263del), causing a frameshift at codon 2534. This creates a premature translational stop signal 6 positions downstream and is expected to result in an absent or disrupted protein product. While this particular variant has not been reported in the literature, truncating variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic. -

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: rs1555286303; hg19: chr13-32930725;