chr17-43093557-C-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_007294.4(BRCA1):c.1974G>C(p.Met658Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000446 in 1,613,890 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M658V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000044 ( 1 hom. )

Consequence

BRCA1
NM_007294.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:15

Conservation

PhyloP100: -1.97

Publications

12 publications found

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 Gene-Disease associations (from GenCC):

breast-ovarian cancer, familial, susceptibility to, 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
Fanconi anemia, complementation group S
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
pancreatic cancer, susceptibility to, 4
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
hereditary breast ovarian cancer syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Fanconi anemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

BRCA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.029901236).

BP6

Variant 17-43093557-C-G is Benign according to our data. Variant chr17-43093557-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 54425.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4 link	c.1974G>C	p.Met658Ile	missense_variant	Exon 10 of 23	ENST00000357654.9	NP_009225.1	P38398-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9 link	c.1974G>C	p.Met658Ile	missense_variant	Exon 10 of 23	1	NM_007294.4	ENSP00000350283.3		P38398-1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00202

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

GnomAD2 exomes

AF:

0.0000597

AC:

AN:

251078

AF XY:

0.0000737

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00149

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000438

AC:

AN:

1461726

Hom.:

Cov.:

AF XY:

0.0000344

AC XY:

AN XY:

727168

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00195

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53312

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000630

AC:

AN:

1111980

Other (OTH)

AF:

0.0000993

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41444

American (AMR)

AF:

0.00

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000180

Hom.:

Bravo

AF:

0.0000529

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0000577

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:15

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:4

Feb 28, 2014

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

The p.Met658Ile variant has been previously identified in the BIC (n=27 as unknown clinical importance), LOVD (n=1) and Exome Server (n=3 out of 13001 chromosomes) databases and appears to be a low frequency variant. This variant is listed in the dbSNP database (ID#:rs55678461) but no frequency information was provided, and so the prevalence of this variant in the general population is not known. It was reported once in the literature in an in silico study where conservation and biophysical properties of the variant were analyzed and used for classification. The variant was predicted to be neutral (Abkevich_2004_15235020). This residue is not conserved in mammals and computational analyses (SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. However, our lab has previously identified this variant in one individual who also had a second pathogenic variant and increasing the likelihood this variant is benign. Myriad genetics has reported this variant as a polymorphism in Jan 2010. In summary, based on the above information this variant is classified as a benign variant. -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 28, 2016

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 03, 2024

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: BRCA1 c.1974G>C (p.Met658Ile) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 251078 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome (6e-05 vs 0.001), allowing no conclusion about variant significance. c.1974G>C has been reported in the literature in individuals affected with Hereditary Breast and/or Ovarian Cancer (example, Judkins_2005, Lu_2012, Li_2014). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least one co-occurrence with another pathogenic variant has been reported in the BIC database (BRCA1 c.66_67delAG (c.68_69del), p.Glu23fs), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. The following publications have been ascertained in the context of this evaluation (PMID: 15235020, 12531920, 16267036, 24675476, 22476429, 15571721, 15385441, 15001988). ClinVar contains an entry for this variant (Variation ID: 54425). Based on the evidence outlined above, the variant was classified as likely benign. -

Hereditary cancer-predisposing syndrome

Benign:5

Mar 11, 2025

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BP1_Strong c.1974G>C, located in exon 10 (11 according to BIC nomenclature) of the BRCA1 gene, is predicted to result in the substitution of metionine by isoleucine at codon 658, p.(Met658Ile).This position is outside a (potentially) clinically important functional domain and the SpliceAI algorithm predicts no significant impact on splicing (BP1_Strong). This variant is found in 15/267940, at a frequency of 0.005% (14/9564 in Ashkenazy Jewish) in the gnomAD v2.1.1 database, exome non-cancer data set. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in the ClinVar database (3x uncertain significance, 9x likely benign, 4x benign) and LOVD (1x likely benign, 3x not classified) and in BRCA Exchange database as not yet reviewed. Based on currently available information, the variant c.1974G>C is classified as a likely benign according to ClinGen-BRCA1 and BRCA2 Guidelines version 1.0.0. -

Dec 11, 2018

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jul 15, 2021

Sema4, Sema4

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Mar 23, 2023

University of Washington Department of Laboratory Medicine, University of Washington

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:curation

Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -

Jun 08, 2015

Color Diagnostics, LLC DBA Color Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breast-ovarian cancer, familial, susceptibility to, 1

Uncertain:2Benign:1

Jan 19, 2016

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Mar 08, 2024

Molecular Pathology, Peter Maccallum Cancer Centre

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA1)

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Mar 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 19, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary breast ovarian cancer syndrome

Benign:2

Jan 17, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 20, 2024

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Met658Ile variant is observed in 15/10,072 (0.1489%) alleles from individuals of gnomAD Ashkenazi Jewish background in gnomAD, which is greater than expected for the disorder. There is a small physicochemical difference between methionine and isoleucine, which is not likely to impact secondary protein structure as these residues share similar properties. The gene BRCA1 has a low rate of benign missense variation as indicated by a high missense variants Z-Score of 2.32. The gene BRCA1 contains 248 pathogenic missense variants, indicating that missense variants are a common mechanism of disease in this gene. The p.Met658Ile missense variant is predicted to be tolerated by both SIFT or PolyPhen2. The isoleucine residue at codon 658 of BRCA1 is present in Bushbaby and 6 other mammalian species. The nucleotide c.1974 in BRCA1 is not conserved according to a GERP++ and PhyloP analysis of 100 vertebrates. For these reasons, this variant has been classified as Benign. -

BRCA1-related disorder

Benign:1

Sep 22, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.0089

BayesDel_noAF

Benign

-0.25

CADD

Benign

0.11

(source)

DANN

Benign

0.78

DEOGEN2

Benign

0.24

T;.;.;.;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.050

LIST_S2

Benign

0.83

T;T;T;T;T

M_CAP

Benign

0.059

MetaRNN

Benign

0.030

T;T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.98

L;L;.;.;.

PhyloP100

-2.0

PrimateAI

Benign

0.27

PROVEAN

Benign

-2.2

N;N;N;N;.

REVEL

Uncertain

0.43

Sift

Benign

0.20

T;T;T;T;.

Sift4G

Benign

0.22

T;T;T;T;.

Polyphen

0.0010

B;.;.;B;.

Vest4

0.26

MutPred

0.29

Loss of MoRF binding (P = 0.0982);Loss of MoRF binding (P = 0.0982);.;Loss of MoRF binding (P = 0.0982);.;

MVP

0.24

MPC

0.091

ClinPred

0.026

GERP RS

-2.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.048

gMVP

0.086

Mutation Taster

=85/15

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over