chr17-43115767-G-C

Position:

chr17-43115767-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BP6

The NM_007294.4(BRCA1):c.93C>G(p.Ile31Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,056 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

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

Consequence

BRCA1
NM_007294.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3O:1

Conservation

PhyloP100: 1.36

Variant links:

Genes affected

BRCA1 (HGNC:1100): (BRCA1 DNA repair associated) This gene encodes a 190 kD nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The BRCA1 gene contains 22 exons spanning about 110 kb of DNA. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2020]

BRCA1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM1

In a zinc_finger_region RING-type (size 41) in uniprot entity BRCA1_HUMAN there are 65 pathogenic changes around while only 6 benign (92%) in NM_007294.4

PM2

Very rare variant in population databases, with high coverage;

BP6

Variant 17-43115767-G-C is Benign according to our data. Variant chr17-43115767-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 55760.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, not_provided=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4 linkuse as main transcript	c.93C>G	p.Ile31Met	missense_variant	3/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9 linkuse as main transcript	c.93C>G	p.Ile31Met	missense_variant	3/23	1	NM_007294.4	ENSP00000350283	P4	P38398-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152056

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:

0.00000399

AC:

AN:

250748

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135526

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152056

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74286

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

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1

Uncertain:1Other:1

not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jun 08, 2016

Variant summary: The BRCA1 c.93C>G (p.Ile31Met) variant involves the alteration of a non-conserved nucleotide and results in a replacement of an Isoleucine located in the central RING domain of BRCA1 with a Methionine. 2/3 in silico tools predict a damaging outcome (SNPs&GO and mutation taster not captured due to low reliability index) for this substitution. This variant was found in 1/112524 control chromosomes at a frequency of 0.0000089, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). It was reported in three probands from HBOC families, however without co-segregation and co-occurrence information, therefore these occurrences do not allow establishment of a cause effect relationship between the variant and the disease. Functional studies demonstrated the variant to be proficient in BARD1 and UbcH5a binding, to be radiation resistant and to decrease E3 activity of BRCA1. Most importantly, the variant was shown not to have a significant impact on homology directed repair activity of BRCA1 which is essential for its tumor suppressing function. The functional studies indicate the variant to be in the neutral spectrum; however, due to lack of stronger clinical information about variant carries, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 10, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Hereditary cancer-predisposing syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Feb 22, 2018

- -

Hereditary breast ovarian cancer syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 24, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.12

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.24

.;T;.;.;.;T;.;T;T;.;T;T;.

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.83

T;T;T;T;T;T;T;T;T;D;T;T;D

M_CAP

Uncertain

0.22

MetaRNN

Uncertain

0.57

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

MetaSVM

Uncertain

0.061

MutationAssessor

Benign

-0.23

N;N;N;N;N;.;.;.;.;.;.;.;.

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.71

PROVEAN

Benign

0.040

N;N;N;N;N;N;N;.;N;N;N;N;N

REVEL

Uncertain

0.56

Sift

Benign

0.42

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

Sift4G

Benign

0.095

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

Polyphen

0.99, 1.0, 0.97

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

Vest4

0.69

MutPred

0.69

Loss of methylation at K32 (P = 0.022);Loss of methylation at K32 (P = 0.022);Loss of methylation at K32 (P = 0.022);Loss of methylation at K32 (P = 0.022);Loss of methylation at K32 (P = 0.022);Loss of methylation at K32 (P = 0.022);Loss of methylation at K32 (P = 0.022);Loss of methylation at K32 (P = 0.022);Loss of methylation at K32 (P = 0.022);Loss of methylation at K32 (P = 0.022);Loss of methylation at K32 (P = 0.022);Loss of methylation at K32 (P = 0.022);Loss of methylation at K32 (P = 0.022);

MVP

0.92

MPC

0.41

ClinPred

0.75

GERP RS

4.0

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.6

Varity_R

0.47

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

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