17-43094534-T-C

Position:

chr17-43094534-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 4P and 10B. PM1PM2BP4_ModerateBP6_Very_Strong

The NM_007294.4(BRCA1):c.997A>G(p.Thr333Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,956 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:3B:4

Conservation

PhyloP100: 0.549

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:

BRCA1 (HGNC:):

BRCA1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PM1

In a region_of_interest Disordered (size 32) in uniprot entity BRCA1_HUMAN there are 17 pathogenic changes around while only 6 benign (74%) in NM_007294.4

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13811237).

BP6

Variant 17-43094534-T-C is Benign according to our data. Variant chr17-43094534-T-C is described in ClinVar as [Benign]. Clinvar id is 184709.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43094534-T-C is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4 linkuse as main transcript	c.997A>G	p.Thr333Ala	missense_variant	10/23	ENST00000357654.9	NP_009225.1	P38398-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9 linkuse as main transcript	c.997A>G	p.Thr333Ala	missense_variant	10/23	1	NM_007294.4	ENSP00000350283.3		P38398-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152148

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461808

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727200

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152148

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74340

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Uncertain:3Benign:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 16, 2023	Published functional studies demonstrate no damaging effect: functionally neutral in three homologous recombination repair complementation assays (Bouwman et al., 2020); Observed in an individual with breast and/or ovarian cancer (Santonocito et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 1116A>G; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24389207, 18680205, 32546644, 32438681, 31131967) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 30, 2018	- -

Breast-ovarian cancer, familial, susceptibility to, 1

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Benign, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Jun 18, 2019	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000013 -

Hereditary cancer-predisposing syndrome

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 10, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 17, 2023	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. -

Hereditary breast ovarian cancer syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 17, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Uncertain

0.42

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

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.071

LIST_S2

Benign

0.78

T;T;T;T;T;T;T;T;T

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.14

T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.055

MutationAssessor

Benign

1.4

L;L;.;.;.;.;.;.;.

PrimateAI

Benign

0.25

PROVEAN

Uncertain

-2.4

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

REVEL

Uncertain

0.51

Sift

Benign

0.19

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

Sift4G

Benign

0.21

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

Polyphen

0.0090

B;.;.;B;.;.;.;.;.

Vest4

0.35

MutPred

0.20

Loss of phosphorylation at T333 (P = 0.0255);Loss of phosphorylation at T333 (P = 0.0255);.;Loss of phosphorylation at T333 (P = 0.0255);.;Loss of phosphorylation at T333 (P = 0.0255);.;.;Loss of phosphorylation at T333 (P = 0.0255);

MVP

0.48

MPC

0.10

ClinPred

0.040

GERP RS

0.64

Varity_R

0.073

gMVP

0.099

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