rs80356944

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_007294.4(BRCA1):c.3587C>T(p.Thr1196Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,614,094 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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. T1196K) has been classified as Uncertain significance.

Frequency

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

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:15B:1

Conservation

PhyloP100: 0.135

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11410743).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4 linkuse as main transcript	c.3587C>T	p.Thr1196Ile	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.3587C>T	p.Thr1196Ile	missense_variant	10/23	1	NM_007294.4	P4	P38398-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152186

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:

0.00316

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250882

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135660

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

AF:

6.84e-7

AC:

AN:

1461790

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727186

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152304

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74482

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

Bravo

AF:

0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:15Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1

Uncertain:6

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 31, 2016	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Nov 25, 2004	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jun 13, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 25, 2023	This missense variant replaces threonine with isoleucine at codon 1196 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in 5 individuals affected with breast or ovarian cancer (PMID: 24372583, 29297111, 34646395, 35402282). This variant has been identified in 1/250882 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may be associated with disease, additional functional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, no assertion criteria provided	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	May 05, 2023	A variant of uncertain significance was detected in this sample , This sequence change replaces threonine with isoleucine at codon 1196 of the BRCA1 protein (p.Thr1196Ile). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is not present in population databases (GenomAD). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 24372583, 27211102, 29297111). ClinVar contains an entry for this variant (Variation ID: 54926). Ten ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "uncertain significance.". In addition, this alteration is predicted to be tolerated by in silico analysis. 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. -

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 17, 2024	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 3706C>T; This variant is associated with the following publications: (PMID: 24372583, 27211102, 26295337, 29297111, 10923033, 23704879, 34646395, 31131967, 29884841, 35402282, 32377563, 37335020, 35171259) -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:1

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). -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 22, 2023	This missense variant replaces threonine with isoleucine at codon 1196 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in 5 individuals affected with breast or ovarian cancer (PMID: 24372583, 29297111, 34646395, 35402282). This variant has been identified in 1/250882 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may be associated with disease, additional functional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 03, 2022	The p.T1196I variant (also known as c.3587C>T), located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 3587. The threonine at codon 1196 is replaced by isoleucine, an amino acid with similar properties. This variant was detected in one suspected-HBOC family from Tunisia (Riahi A et al, Clin. Genet. 2015 Feb; 87(2):155-60), in a cohort of 173 Arab breast and ovarian cancer patients (Alhuqail AJ et al. Breast Cancer Res Treat, 2018 Apr;168:695-702), and in a cohort of 30 Moroccan women with early onset triple negative breast cancer (Laraqui A et al. J Genomics, 2021 Sep;9:43-54). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 11, 2022	Variant summary: BRCA1 c.3587C>T (p.Thr1196Ile) results in a non-conservative amino acid change in the encoded protein sequence. Four 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 250882 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3587C>T, has been reported in the literature in an individual affected with Breast and/or Ovarian Cancer (example, Riahi_2015, Riahi_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -

BRCA1-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 23, 2023

The BRCA1 c.3587C>T variant is predicted to result in the amino acid substitution p.Thr1196Ile. This variant has been reported in individuals with breast and/or ovarian cancer (Table 2, Riahi et al. 2015. PubMed: 24372583; Table 4, Riahi et al. 2016. PubMed ID: 27211102; Table S5, Alhuqail et al. 2018. PubMed ID: 29297111; Table 4, Laraqui et al. 2021. PubMed ID: 34646395). This variant is reported in 1 of ~251,000 alleles in gnomAD (http://gnomad.broadinstitute.org/variant/17-41243961-G-A). It is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/54926/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary breast ovarian cancer syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1196 of the BRCA1 protein (p.Thr1196Ile). This variant is present in population databases (rs80356944, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 24372583, 27211102, 29297111, 34646395, 35171259). ClinVar contains an entry for this variant (Variation ID: 54926). 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%. 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

0.15

BayesDel_addAF

Uncertain

0.072

BayesDel_noAF

Benign

-0.13

CADD

Benign

7.3

DANN

Benign

0.94

DEOGEN2

Benign

0.39

T;.;.;.

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.80

T;T;T;T

M_CAP

Benign

0.036

MetaRNN

Benign

0.11

T;T;T;T

MetaSVM

Benign

-0.84

MutationAssessor

Uncertain

2.3

M;M;.;.

MutationTaster

Benign

1.0

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

PrimateAI

Benign

0.26

PROVEAN

Uncertain

-3.2

D;D;D;D

REVEL

Uncertain

0.37

Sift

Benign

0.046

D;D;D;D

Sift4G

Benign

0.089

T;T;T;T

Polyphen

0.054

B;.;.;B

Vest4

0.34

MutPred

0.32

Loss of catalytic residue at T1196 (P = 0.0605);Loss of catalytic residue at T1196 (P = 0.0605);.;Loss of catalytic residue at T1196 (P = 0.0605);

MVP

0.48

MPC

0.11

ClinPred

0.10

GERP RS

2.2

Varity_R

0.048

gMVP

0.13

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