17-61861530-T-C

Position:

chr17-61861530-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_032043.3(BRIP1):c.10A>G(p.Met4Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 1,610,412 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M4I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

BRIP1
NM_032043.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:2

Conservation

PhyloP100: -2.16

Variant links:

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]

BRIP1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.019673139).

BP6

Variant 17-61861530-T-C is Benign according to our data. Variant chr17-61861530-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 232285.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRIP1	NM_032043.3 linkuse as main transcript	c.10A>G	p.Met4Val	missense_variant	2/20	ENST00000259008.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRIP1	ENST00000259008.7 linkuse as main transcript	c.10A>G	p.Met4Val	missense_variant	2/20	1	NM_032043.3	P2	Q9BX63-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

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:

0.00000398

AC:

AN:

251232

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135782

show subpopulations

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000219

AC:

AN:

1458262

Hom.:

Cov.:

AF XY:

0.0000207

AC XY:

AN XY:

725788

show subpopulations

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:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000253

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74316

show subpopulations

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:

0.0000113

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 23, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 12, 2018	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Aug 12, 2024

Variant summary: BRIP1 c.10A>G (p.Met4Val) results in a conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251232 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.10A>G has been reported in the literature in individuals with a diagnosis of or predisposition to hereditary cancer (e.g. Tsaousis_2019, Shao_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Fanconi Anemia Complementation Group J. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31742824, 31159747). ClinVar contains an entry for this variant (Variation ID: 232285). 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

Dec 21, 2023

This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 4 of the BRIP1 protein (p.Met4Val). This variant is present in population databases (rs45512093, gnomAD 0.003%). This missense change has been observed in individual(s) with a personal or family history of breast and/or ovarian cancer or clinical features of Lynch syndrome (PMID: 25980754, 26921362, 31159747). ClinVar contains an entry for this variant (Variation ID: 232285). 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%. 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. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 28, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer or a history of Lynch syndrome-associated cancer and/or colon polyps (Yurgelun et al., 2015; Easton et al., 2016); This variant is associated with the following publications: (PMID: 25980754, 31159747, 26921362, 31742824) -

Malignant tumor of breast

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The BRIP1 p.Met4Val variant was identified in 2 of 5146 proband chromosomes (frequency: 0.0004) from individuals or families with breast cancer or lynch syndrome and was not identified in 2246 control chromosomes from healthy individuals (Easton 2016, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs45512093) as "With Uncertain significance allele", ClinVar (classified as likely benign by Ambry Genetics; as uncertain significance by Invitae), MutDB, and in the Zhejiang University database. The variant was identified in control databases in 2 of 277002 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: European in 1 of 126564 chromosomes (freq: 0.00001), and South Asian in 1 of 30780 chromosomes (freq: 0.00003); but was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, and Finnish populations. The p.Met4 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.052

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.46

CADD

Benign

0.0030

DANN

Benign

0.47

DEOGEN2

Benign

0.061

T;.;.

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.010

LIST_S2

Benign

0.26

T;T;T

M_CAP

Benign

0.043

MetaRNN

Benign

0.020

T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-1.6

N;N;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.21

PROVEAN

Benign

0.070

N;.;.

REVEL

Benign

0.12

Sift

Benign

1.0

T;.;.

Sift4G

Benign

1.0

T;T;.

Polyphen

0.0

B;.;.

Vest4

0.045

MutPred

0.20

Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);

MVP

0.29

MPC

0.16

ClinPred

0.025

GERP RS

-8.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.049

gMVP

0.35

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over