17-61743048-T-C

Position:

• chr17-61743048-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_032043.3(BRIP1):​c.2344A>G​(p.Ile782Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000297 in 1,613,908 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000032 (0 hom.)
• Consequence: BRIP1 NM_032043.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:12
• Conservation: PhyloP100: 0.721

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_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11720559).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRIP1	NM_032043.3	c.2344A>G	p.Ile782Val	missense_variant	16/20	ENST00000259008.7	NP_114432.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRIP1	ENST00000259008.7	c.2344A>G	p.Ile782Val	missense_variant	16/20	1	NM_032043.3	ENSP00000259008	P2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251332 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135828

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000322 AC: 47 AN: 1461726 Hom.: 0 Cov.: 31 AF XY: 0.0000330 AC XY: 24 AN XY: 727164

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000387

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152182 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74356

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Division of Medical Genetics, University of Washington	Dec 06, 2018	The c.2344A>G missense variant has been identified in individuals with breast cancer and pancreatic cancer (Easton 2016, Shindo 2017), but has not to our knowledge been reported in an individual with ovarian cancer. The vast majority of pathogenic variants reported in the BRIP1 gene to date are truncating variants. The c.2344A>G variant has an allele frequency of 0.000008 in the Broad Institute ExAC Browser (http://exac.broadinstitute.org/). Thus, it is unknown at this time whether this variant increases cancer risk. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 22, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 01, 2023	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 12, 2022	The frequency of this variant in the general population, 0.000008 (2/251332 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals affected with breast cancer and in controls (PMID: 26921362 (2016)) as well as in individuals affected with pancreatic cancer (PMID: 28767289 (2017)). One functional study described this variant as a hypomorph due to the modest reduction in cellular growth observed after high-dose treatment with a DNA damaging agent (PMID: 31822495 (2020)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 17, 2021	Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in individuals with breast or pancreatic cancer (Easton 2016, Shindo 2017); Published functional studies are inconclusive: lack of cisplatin sensitivity but intermediate mitomycin C sensitivity (Moyer 2020); This variant is associated with the following publications: (PMID: 24123366, 26921362, 28767289, 27535533, 31822495) -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 13, 2023	The p.I782V variant (also known as c.2344A>G), located in coding exon 15 of the BRIP1 gene, results from an A to G substitution at nucleotide position 2344. The isoleucine at codon 782 is replaced by valine, an amino acid with highly similar properties. This alteration has been reported in cohorts of breast, pancreatic, and ovarian cancer patients, as well as in a control (Easton DF et al. J Med Genet, 2016 05;53:298-309; Shindo K et al. J. Clin Oncol, 2017 Oct;35:3382-3390; Moyer CL et al. Cancer Res, 2020 02;80:857-867). In an inter-strand cross link damage survival assay, the p.I782V alteration was found to be functionally hypomorphic (Moyer CL et al. Cancer Res, 2020 02;80:857-867). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 13, 2023	This missense variant replaces isoleucine with valine at codon 782 of the BRIP1 protein. Computational prediction suggests that this variant may not impact protein structure and function. A functional study has reported that this variant resulted in hymomorphic activity in a mitomycin C sensitivity assay (PMID: 31822495). This variant has been detected in individuals affected with pancreatic cancer (PMID: 28767289, 32659497) and in 10/101759 breast cancer and 1/15587 ovarian cancer cases (PMID: 31822495). This variant also has been reported in the general population (PMID: 31822495) and in 1 individual age 70 years or older without cancer in the FLOSSIES database (https://whi.color.com/variant/17-59820409-T-C). A breast cancer case-control meta-study has been detected this variant in 3/60466 cases and 2/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRIP1_000419). This variant has been identified in 2/251332 chromosomes 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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Nov 16, 2023

Variant summary: BRIP1 c.2344A>G (p.Ile782Val) results in a conservative amino acid change located in the ATP-dependent helicase, C-terminal domain (IPR006555) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251332 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2344A>G has been reported in the literature, primarily as a VUS in settings of multigene panel testing, in individuals affected with pancreatic, breast, and ovarian cancers, and also in at least one control individual (e.g. Easton_2016, Shindo_2017, Moyer_2020, Bhai_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. A functional study evaluated the effect of the variant using a transient DNA damage-based rescue assay and categorized the variant as hypomorphic (Moyer_2020); however, this does not allow strong conclusions about the variant effect. The following publications have been ascertained in the context of this evaluation (PMID: 34326862, 31822495, 28767289, 26921362). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. 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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 782 of the BRIP1 protein (p.Ile782Val). This variant is present in population databases (rs142806416, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer and/or pancreatic cancer (PMID: 26921362, 28767289, 34326862). ClinVar contains an entry for this variant (Variation ID: 142346). 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: 31822495). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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. -

Fanconi anemia complementation group J Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Aug 30, 2016

- -

Ovarian neoplasm Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Aug 30, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	13
DANN	Benign	0.82
DEOGEN2	Benign	0.35	T;.
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.81	T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	-0.73	N;N
MutationTaster	Benign	0.61	D;D
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.38	N;.
REVEL	Benign	0.28
Sift	Benign	1.0	T;.
Sift4G	Benign	1.0	T;T
Polyphen		0.011	B;.
Vest4		0.14
MVP		0.67
MPC		0.17
ClinPred		0.026	T
GERP RS		-1.2
Varity_R		0.025
gMVP		0.31

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: rs142806416; hg19: chr17-59820409;