rs386576380

chr17-43106487-A-Tchr17-43106487-A-Cchr17-43106487-A-G

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2_SupportingPM5PP3_StrongPP5_Very_Strong

The NM_007294(BRCA1):c.181T>A(p.Cys61Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD Genomes project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C61F) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

BRCA1
NM_007294 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2O:1

Conservation

PhyloP100: 5.10

Links

BRCA1 (HGNC:1100):

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 17 uncertain in NM_007294

PM2

Very rare variant; Number of alleles below threshold, Median coverage is 32.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-43106487-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 17661. Status of the report is reviewed_by_expert_panel, 3 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.988

PP5

Variant 17:43106487-A>T is Pathogenic according to our data. Variant chr17-43106487-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 54359. Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-43106487-A-T is described in Lovd as [Pathogenic]. Variant chr17-43106487-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4 linkuse as main transcript	c.181T>A	p.Cys61Ser	missense_variant	4/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9 linkuse as main transcript	c.181T>A	p.Cys61Ser	missense_variant	4/23	1	NM_007294.4	P2	P38398-1

Frequencies

GnomAD3 genomes

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1

Pathogenic:2Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Molecular Diagnostics, Institute of Oncology Ljubljana	Apr 02, 2020	- -
not provided, no assertion provided	in vitro	Brotman Baty Institute, University of Washington	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.56

Cadd

Uncertain

Dann

Uncertain

0.99

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.96

D;D;D;D;D;D;D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.96

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.95

MutationAssessor

Pathogenic

4.0

H;H;H;H;.;H;.;.;.;.;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D;N;N;N;N;N

PrimateAI

Uncertain

0.68

PROVEAN

Benign

0.030

N;N;N;N;N;N;D;N;N;.;N;N;D;.

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

D;D;D;D;D;D;D;D;D;.;D;D;D;.

Sift4G

Uncertain

0.031

D;D;D;T;D;T;.;T;D;.;D;D;.;.

Polyphen

0.48, 1.0, 1.0

.;P;.;.;.;D;.;.;D;.;.;.;.;.

Vest4

0.97

MutPred

0.94

Gain of disorder (P = 0.013);Gain of disorder (P = 0.013);Gain of disorder (P = 0.013);Gain of disorder (P = 0.013);.;Gain of disorder (P = 0.013);Gain of disorder (P = 0.013);.;Gain of disorder (P = 0.013);Gain of disorder (P = 0.013);Gain of disorder (P = 0.013);Gain of disorder (P = 0.013);Gain of disorder (P = 0.013);.;

MVP

0.99

MPC

0.42

ClinPred

1.0

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.99

gMVP

0.89

Splicing

Find out SpliceAI 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

Links

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over