chr17-43091820-T-C

Position:

chr17-43091820-T-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_007294.4(BRCA1):c.3711A>G(p.Ile1237Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,614,046 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. 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. I1237T) has been classified as Likely benign.

Frequency

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

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10B:5

Conservation

PhyloP100: -0.129

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.087765425).

BP6

Variant 17-43091820-T-C is Benign according to our data. Variant chr17-43091820-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 54973.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=7}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4 linkuse as main transcript	c.3711A>G	p.Ile1237Met	missense_variant	10/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9 linkuse as main transcript	c.3711A>G	p.Ile1237Met	missense_variant	10/23	1	NM_007294.4	P4	P38398-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152168

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

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251284

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135794

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:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461878

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000719

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74338

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

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Uncertain significance, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 23, 2022	DNA sequence analysis of the BRCA1 gene demonstrated a sequence change, c.3711A>G, in exon 10 that results in an amino acid change, p.Ile1237Met. This sequence change has been previously described in individuals with personal and/or family history of breast and/or ovarian cancer, colorectal cancer and papillary serous carcinoma of the peritoneum and (PMID: 10728699, 24884479, 25896959, 27062684). This sequence change has been described in the gnomAD database in one individual which corresponds to a population frequency of 0.0004% (dbSNP rs80357388). The p.Ile1237Met change affects a poorly conserved amino acid residue located in a domain of the BRCA1 protein that is known to be functional. The p.Ile1237Met substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Ile1237Met change remains unknown at this time. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 18, 2022	Variant summary: BRCA1 c.3711A>G (p.Ile1237Met) 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 4e-06 in 251284 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3711A>G has been reported in the literature as a VUS in settings of individuals affected with and/or undergoing testing for a variety of cancers (example, Dargenio_2015, Schorge_2000, Silva_2014, Azzollini_2016, Fountzilas_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function (Bouwman_2020). These results showed no damaging effect of this variant on ability to complement BRCA1-deficient mouse embryonic stem cells in homologous recombination DNA repair (HRR) using cisplatin and olaparib sensitivity assays and a direct GFP HRR assay. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=2; VUS, n=5). Based on the evidence outlined above, the variant was classified as likely benign. -

Breast-ovarian cancer, familial, susceptibility to, 1

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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, no assertion criteria provided	clinical testing	Department of Medical and Surgical Sciences, University of Bologna	Sep 01, 2023	BS3(Strong)+BP1(Strong) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042) -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Nov 25, 2004	- -

Hereditary cancer-predisposing syndrome

Benign:3

Likely benign, criteria provided, single submitter	curation	University of Washington Department of Laboratory Medicine, University of Washington	Mar 23, 2023	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 31, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 08, 2018	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. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 02, 2024	Observed in individuals with personal or family history of breast or ovarian cancer (PMID: 27062684, 32806537, 25896959, 10728699, 24884479); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Also known as 3830A>G; This variant is associated with the following publications: (PMID: 25896959, 24884479, 10923033, 23704879, 28857155, 10728699, 27062684, 32546644, 23469205, 31911673, 32806537) -

Breast and/or ovarian cancer

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Oct 20, 2021

- -

Breast neoplasm

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

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

- -

Malignant tumor of breast

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The p.Ile1237Met variant was not identified in the literature. The variant was identified in dbSNP (ID: rs80357388) â€šÃ„ÃºWith Uncertain significance alleleâ€šÃ„Ã¹, the ClinVar database (classified with uncertain significance by Ambry Genetics), the BIC database (1X with unknown clinical importance), and UMD (1X as an unclassified variant).The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. However, this information is not predictive enough to rule out pathogenicity. The p.Ile1237 residue is not conserved in mammals and the variant methionine (Met) is present in dog, increasing the likelihood this variant doesn't have clinical significance. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance. -

Hereditary breast ovarian cancer syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 14, 2023

This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1237 of the BRCA1 protein (p.Ile1237Met). This variant is present in population databases (rs80357388, gnomAD 0.0009%). This missense change has been observed in individual(s) with papillary serous carcinoma of the peritoneum and personal and/or family history of breast and/or ovarian cancer (PMID: 10728699, 24884479, 25896959, 27062684). This variant is also known as 3830A>G. ClinVar contains an entry for this variant (Variation ID: 54973). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 32546644). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.010

BayesDel_noAF

Benign

-0.25

CADD

Benign

3.7

DANN

Benign

0.29

DEOGEN2

Benign

0.11

T;.;.;.

Eigen

Benign

-0.89

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.060

LIST_S2

Benign

0.71

T;T;T;T

M_CAP

Benign

0.030

MetaRNN

Benign

0.088

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

N;N;.;.

MutationTaster

Benign

1.0

N;N;N;N;N;N;N;N;N;N;N;N;N;N

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.18

N;N;N;N

REVEL

Uncertain

0.40

Sift

Benign

0.060

T;T;T;T

Sift4G

Benign

0.18

T;T;T;T

Polyphen

0.013

B;.;.;B

Vest4

0.32

MutPred

0.18

Gain of ubiquitination at K1233 (P = 0.056);Gain of ubiquitination at K1233 (P = 0.056);.;Gain of ubiquitination at K1233 (P = 0.056);

MVP

0.54

MPC

0.13

ClinPred

0.017

GERP RS

-1.0

Varity_R

0.049

gMVP

0.073

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