17-61808488-C-T

Variant names:

• chr17-61808488-C-T
• rs137852985
• NM_032043.3:c.897G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_032043.3(BRIP1):​c.897G>A​(p.Met299Ile) variant causes a missense 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: 32)
• Consequence: BRIP1 NM_032043.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:4
• Conservation: PhyloP100: 2.76

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRIP1	NM_032043.3	c.897G>A	p.Met299Ile	missense_variant	Exon 7 of 20	ENST00000259008.7	NP_114432.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRIP1	ENST00000259008.7	c.897G>A	p.Met299Ile	missense_variant	Exon 7 of 20	1	NM_032043.3	ENSP00000259008.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Feb 18, 2021

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces methionine with isoleucine at codon 299 of the BRIP1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown that this variant protein displays ATPase and helicase activities similar to or greater than the wild-type protein (PMID: 14983014, 17145708) and is able to complement DNA binding, helicase, and DNA damage repair activities to a similar extent as the wild-type protein in BRIP1 knock-out cell lines (PMID: 32542039). This variant has been reported in an individual affected with breast cancer (PMID: 11301010). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Apr 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.M299I variant (also known as c.897G>A), located in coding exon 6 of the BRIP1 gene, results from a G to A substitution at nucleotide position 897. The methionine at codon 299 is replaced by isoleucine, an amino acid with highly similar properties. In one study, this variant was reported in 1/30 cases with early onset breast cancer but was not observed in 35 cases of familial breast and ovarian cancer, 21 sporadic cases of breast or ovarian cancer, or 200 matched controls (Cantor SB et al. Cell 2001 Apr; 105(1):149-60). Several in vitro assays demonstrated that this alteration does not result in loss-of-function but exerts a modest gain-of-function effect on ATP-dependent activity compared to wildtype (Cantor S et al. Proc. Natl. Acad. Sci. U.S.A. 2004 Feb; 101(8):2357-62; Gupta R et al. Nucleic Acids Res. 2006; 34(22):6673-83; Gupta R et al. Blood 2007 Oct; 110(7):2390-8; Wu Y et al. Mol. Cell. Biol. 2008 Jun; 28(12):4116-28; Sommers JA et al. J. Biol. Chem. 2009 Mar; 284(12):7505-17). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Breast cancer, early-onset Pathogenic:1

Apr 19, 2019

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not specified Uncertain:1

Oct 16, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRIP1 c.897G>A (p.Met299Ile) results in a conservative amino acid change located in the Helicase-like, DEXD box c2 type (IPR006554) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 250858 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.897G>A has been reported in the literature in individuals affected with breast cancer and Acute myeloid leukaemia (Cantor_2001, Yang_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Fanconi Anemia Complementation Group J. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed intacted iron incorporation ability and restoring MMC sensitivity of FANCJ knock-out cells to the same extent as expression of the wild-type (Odermatt_2020), which is conflict with the previous report of elevated ATPase activity in vitro (Cantor_2004). The following publications have been ascertained in the context of this evaluation (PMID: 11301010, 14983014, 32542039, 34482403). ClinVar contains an entry for this variant (Variation ID: 4737). Based on the evidence outlined above, the variant was classified as uncertain significance. -

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

Mar 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 299 of the BRIP1 protein (p.Met299Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with early-onset breast cancer (PMID: 11301010). ClinVar contains an entry for this variant (Variation ID: 4737). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRIP1 protein function with a negative predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on BRIP1 function (PMID: 14983014, 17145708, 32542039). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T;.
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.048	D
MetaRNN	Uncertain	0.63	D;D
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.69	N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.8	N;.
REVEL	Uncertain	0.37
Sift	Benign	0.057	T;.
Sift4G	Benign	0.10	T;T
Polyphen		0.83	P;.
Vest4		0.32
MutPred		0.84		Loss of helix (P = 0.0626);Loss of helix (P = 0.0626);
MVP		0.72
MPC		0.20
ClinPred		0.76	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs137852985; hg19: chr17-59885849;