17-43049179-A-G

Position:

chr17-43049179-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1BP6

The NM_007294.4(BRCA1):c.5348T>C(p.Met1783Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000929 in 1,614,158 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. M1783K) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00052 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000049 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:13O:1

Conservation

PhyloP100: 5.13

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM1

In a domain BRCT 2 (size 99) in uniprot entity BRCA1_HUMAN there are 69 pathogenic changes around while only 15 benign (82%) in NM_007294.4

BP6

Variant 17-43049179-A-G is Benign according to our data. Variant chr17-43049179-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 37659.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=8, Uncertain_significance=2, not_provided=1, Benign=3}. Variant chr17-43049179-A-G is described in Lovd as [Benign]. Variant chr17-43049179-A-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4 linkuse as main transcript	c.5348T>C	p.Met1783Thr	missense_variant	21/23	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.5348T>C	p.Met1783Thr	missense_variant	21/23	1	NM_007294.4	ENSP00000350283.3		P38398-1

Frequencies

GnomAD3 genomes

AF:

0.000519

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00176

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.00

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000119

AC:

AN:

251442

Hom.:

AF XY:

0.0000883

AC XY:

AN XY:

135878

show subpopulations

Gnomad AFR exome

AF:

0.00166

Gnomad AMR exome

AF:

0.0000578

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:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000486

AC:

AN:

1461844

Hom.:

Cov.:

AF XY:

0.0000468

AC XY:

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.00155

Gnomad4 AMR exome

AF:

0.000134

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:

0.00

Gnomad4 OTH exome

AF:

0.000215

GnomAD4 genome

AF:

0.000519

AC:

AN:

152314

Hom.:

Cov.:

AF XY:

0.000591

AC XY:

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.00176

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000280

Hom.:

Bravo

AF:

0.000518

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000173

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:13Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary breast ovarian cancer syndrome

Uncertain:1Benign:3

Uncertain significance, criteria provided, single submitter	research	Genetics Program, Instituto Nacional de Cancer	Nov 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	Apr 19, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Apr 25, 2016	- -

Breast-ovarian cancer, familial, susceptibility to, 1

Uncertain:1Benign:2Other:1

Benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Aug 05, 2009	- -
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)	Feb 20, 2004	- -
Likely benign, criteria provided, single submitter	clinical testing	Pathway Genomics	Oct 30, 2014	- -

Hereditary cancer-predisposing syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 18, 2014	This alteration is classified as 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. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 09, 2015	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	May 10, 2021	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 21, 2022	See Variant Classification Assertion Criteria. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 06, 2016	Variant summary: BRCA1 c.5348C>T is a missense variant that changes a conserved T to C, resulting in an amino acid change from Met to Thr at codon 1783 in the C-terminal BRCT domain of BRCA1. This variant is predicted to be damaging by 5/5 in-silico tools. Functional studies indicate that the variant slightly reduces BRCA1 structural stability, has intermediate phosphopeptide-binding activity, reduced transcriptional activity, and 66% of wild type BRCA1 HDR function.This variant was found in 21/121366 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.001929 (20/10368). This frequency is about 2 times the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. Although this variant was reported in multiple patients in the literature and databases, lack of co-segregation (McKean Cowdin_HumGen_2005) and multiple co-occurrences with pathogenic variants (UMD database) were found in some of these patients/families. In addition, multiple reputable sources classify this variant as likely benign/benign. Taken together, this variant was scored as Benign. -

Breast and/or ovarian cancer

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research

Oct 07, 2013

- -

Breast neoplasm

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 03, 2022

- -

Malignant tumor of breast

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The BRCA1 p.Met1783Thr variant was identified in 2 of 838 proband chromosomes (frequency: 0.002) from individuals or families with breast or ovarian cancer and was not identified in 192 control chromosomes from healthy individuals (McKean-Cowdin 2005, Silva 2014). The variant was also identified in dbSNP (ID: rs55808233) as "With other allele", ClinVar (classified as benign by Invitae, Ambry Genetics, and two other submitters; as likely benign by GeneDx, Color, and two other submitters; and as uncertain significance by five submitters), LOVD 3.0 (15x), and UMD-LSDB (2x as likely neutral). In UMD, the variant was reported with a co-occurring, pathogenic BRCA1 variants c.755_761del (p.Arg252LeufsX44) and c.-200_80del (p.Met1SerfsX13), increasing the likelihood that the p.Met1783Thr variant does not have clinical significance. The variant was identified in control databases in 45 of 277188 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 41 of 24028 chromosomes (freq: 0.002, increasing the likelihood this could be a low frequency benign variant), Other in 2 of 6462 chromosomes (freq: 0.0003), and Latino in 2 of 34420 chromosomes (freq: 0.00006), while it was not observed in the European, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. Although the p.Met1783 residue is not conserved in mammals and other organisms, computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the M variant may impact the protein. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. There are conflicting results in the literature regarding the effect of this variant on the BRCA1 protein, specifically within the BRCT domain where this variant is located. Functional studies demonstrated that the variant may be moderately destabilizing to the protein folding (Drikos 2009, Glover 2006, Williams 2003, Rowling 2010) but that protein binding capabilities of the mutant protein were similar to the wild type (Drikos 2009, Glover 2006) and that the mutant protein retains between 50-70% DNA repair activity relative to the wild type (Gaboriau 2015, Lu 2015). In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Hereditary cancer

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

Jan 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Benign

-0.0045

BayesDel_noAF

Pathogenic

0.21

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.38

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

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.92

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

M_CAP

Pathogenic

0.64

MetaRNN

Uncertain

0.44

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

MetaSVM

Uncertain

0.22

MutationAssessor

Uncertain

2.3

.;M;.;.;.;.;.;.

PrimateAI

Uncertain

0.56

PROVEAN

Pathogenic

-4.5

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

REVEL

Uncertain

0.63

Sift

Uncertain

0.0010

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

Sift4G

Uncertain

0.0020

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

Polyphen

0.99, 1.0

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

Vest4

0.87

MVP

0.94

MPC

0.34

ClinPred

0.12

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.75

gMVP

0.85

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