rs1064792963

Variant names:

• chr13-32394819-A-ACTGATTTGGACCACT
• rs1064792963
• NM_000059.4:c.9387_9388insCTGATTTGGACCACT

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4

The NM_000059.4(BRCA2):​c.9387_9388insCTGATTTGGACCACT​(p.Pro3129_Glu3130insLeuIleTrpThrThr) variant causes a conservative inframe insertion 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: BRCA2 NM_000059.4 conservative_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.39

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000059.4.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.9387_9388insCTGATTTGGACCACT	p.Pro3129_Glu3130insLeuIleTrpThrThr	conservative_inframe_insertion	Exon 25 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.9387_9388insCTGATTTGGACCACT	p.Pro3129_Glu3130insLeuIleTrpThrThr	conservative_inframe_insertion	Exon 25 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.9018_9019insCTGATTTGGACCACT	p.Pro3006_Glu3007insLeuIleTrpThrThr	conservative_inframe_insertion	Exon 25 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*1445_*1446insCTGATTTGGACCACT		non_coding_transcript_exon_variant	Exon 24 of 26	2		ENSP00000506251.1
BRCA2	ENST00000614259	n.*1445_*1446insCTGATTTGGACCACT		3_prime_UTR_variant	Exon 24 of 25	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary breast ovarian cancer syndrome Uncertain:1

May 20, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 409508). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant, c.9387_9388insCTGATTTGGACCACT, results in the insertion of 5 amino acids to the BRCA2 protein (p.Pro3129_Glu3130insLeuIleTrpThrThr), but otherwise preserves the integrity of the reading frame. -

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: rs1064792963; hg19: chr13-32968956;