rs1555618396

chr17-61859822-G-GCAGAACAAAGTAAGGCTAAGCTTTTTCCACTTCCTGTGGGACTCTCCAACAAACAATGTTGCTTGCTGTTTAATCCTCTGAGAATCTATGAA

Variant summary

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

The NM_032043.3(BRIP1):c.178_179insTTCATAGATTCTCAGAGGATTAAACAGCAAGCAACATTGTTTGTTGGAGAGTCCCACAGGAAGTGGAAAAAGCTTAGCCTTACTTTGTTCTG(p.Ala60ValfsTer8) variant causes a stop gained, frameshift change. 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. A60A) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRIP1 NM_032043.3 stop_gained, frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.98

Genes affected

BRIP1 (HGNC:20473): (BRCA1 interacting helicase 1) The protein encoded by this gene is a member of the RecQ DEAH helicase family and interacts with the BRCT repeats of breast cancer, type 1 (BRCA1). The bound complex is important in the normal double-strand break repair function of breast cancer, type 1 (BRCA1). This gene may be a target of germline cancer-inducing mutations. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 12 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 17-61859822-G-GCAGAACAAAGTAAGGCTAAGCTTTTTCCACTTCCTGTGGGACTCTCCAACAAACAATGTTGCTTGCTGTTTAATCCTCTGAGAATCTATGAA is Pathogenic according to our data. Variant chr17-61859822-G-GCAGAACAAAGTAAGGCTAAGCTTTTTCCACTTCCTGTGGGACTCTCCAACAAACAATGTTGCTTGCTGTTTAATCCTCTGAGAATCTATGAA is described in ClinVar as [Pathogenic]. Clinvar id is 407793.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRIP1	NM_032043.3	c.178_179insTTCATAGATTCTCAGAGGATTAAACAGCAAGCAACATTGTTTGTTGGAGAGTCCCACAGGAAGTGGAAAAAGCTTAGCCTTACTTTGTTCTG	p.Ala60ValfsTer8	stop_gained, frameshift_variant	3/20	ENST00000259008.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRIP1	ENST00000259008.7	c.178_179insTTCATAGATTCTCAGAGGATTAAACAGCAAGCAACATTGTTTGTTGGAGAGTCCCACAGGAAGTGGAAAAAGCTTAGCCTTACTTTGTTCTG	p.Ala60ValfsTer8	stop_gained, frameshift_variant	3/20	1	NM_032043.3	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial cancer of breast;C1836860:Fanconi anemia complementation group J Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 14, 2021

This sequence change creates a premature translational stop signal (p.Ala60Valfs*8) in the BRIP1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRIP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 407793). Loss-of-function variants in BRIP1 are known to be pathogenic (PMID: 16116423, 17033622, 21964575). 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: rs1555618396; hg19: chr17-59937183;