17-61683837-G-T

Variant names:

• chr17-61683837-G-T
• rs777213170
• NM_032043.3:c.3209C>A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_032043.3(BRIP1):​c.3209C>A​(p.Ser1070*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRIP1 NM_032043.3 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 3.14

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 Likely_pathogenic. Variant got 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.144 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-61683837-G-T is Pathogenic according to our data. Variant chr17-61683837-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 407856.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRIP1	NM_032043.3	c.3209C>A	p.Ser1070*	stop_gained	Exon 20 of 20	ENST00000259008.7	NP_114432.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRIP1	ENST00000259008.7	c.3209C>A	p.Ser1070*	stop_gained	Exon 20 of 20	1	NM_032043.3	ENSP00000259008.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Jun 07, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 407856). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the TopBP1-binding region of the BRIP1 protein, which plays a critical role in RPA chromatin loading and the activation of the replication checkpoint in response to DNA damage (PMID: 20159562, 21127055). While functional studies have not been performed to directly test the effect of this variant on BRIP1 protein function, this suggests that disruption of this region of the protein is causative of disease. This variant has not been reported in the literature in individuals affected with BRIP1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser1070*) in the BRIP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 180 amino acid(s) of the BRIP1 protein. -

Familial cancer of breast Pathogenic:1

Feb 23, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Oct 20, 2020

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S1070* variant (also known as c.3209C>A) located in coding exon 19 of the BRIP1 gene, results from a C to A substitution at nucleotide position 3209. This changes the amino acid from a serine to a stop codon within coding exon 19. This alteration occurs at the 3' terminus of BRIP1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 180 amino acids of the protein. Premature stop codons are typically deleterious in nature and the impacted C-terminal region of the protein has been shown by structural, biochemical, and mutational analysis to be relevant for the protein function (Leung CC et al. J. Biol. Chem. 2011 Feb; 286(6):4292-301. Xie J et al. PLoS Genet. 2012 Jul; 8(7):e1002786; Gong Z et al. Mol. Cell, 2010 Feb;37:438-46). Based on the majority of available evidence to date, this variant is likely to be pathogenic -

not provided Uncertain:1

Nov 13, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation as the last 180 amino acid(s) are lost; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 25846551, 20159562, 21127055) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	36
DANN	Uncertain	0.98
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Benign	0.70	D
Vest4		0.66
GERP RS		3.6

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: rs777213170; hg19: chr17-59761198; COSMIC: COSV51997305; COSMIC: COSV51997305;