rs80357001

Positions:

Variant summary

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

The NM_001407966.1(BRCA1):c.-197C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000533 in 1,612,488 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000051 ( 0 hom. )

Consequence

BRCA1
NM_001407966.1 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:5

Conservation

PhyloP100: 0.282

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 Likely_benign. Variant got -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.10731056).

BP6

Variant 17-43094839-G-A is Benign according to our data. Variant chr17-43094839-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 55669.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=6}. Variant chr17-43094839-G-A 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.692C>T	p.Thr231Met	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.692C>T	p.Thr231Met	missense_variant	10/23	1	NM_007294.4	ENSP00000350283.3		P38398-1

Frequencies

GnomAD3 genomes

AF:

0.0000790

AC:

AN:

151840

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000657

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.0000949

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000444

AC:

AN:

247512

Hom.:

AF XY:

0.0000521

AC XY:

AN XY:

134326

show subpopulations

Gnomad AFR exome

AF:

0.0000650

Gnomad AMR exome

AF:

0.0000292

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000197

Gnomad FIN exome

AF:

0.0000466

Gnomad NFE exome

AF:

0.0000179

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000507

AC:

AN:

1460648

Hom.:

Cov.:

AF XY:

0.0000619

AC XY:

AN XY:

726570

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000225

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000221

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000432

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.0000790

AC:

AN:

151840

Hom.:

Cov.:

AF XY:

0.0000540

AC XY:

AN XY:

74124

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.0000657

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.0000949

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000772

Hom.:

Bravo

AF:

0.0000831

ExAC

AF:

0.0000660

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 14, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 09, 2022	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 19, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate no damaging effect: no effect on expression level of full-length transcript, but was found to increase the level of a naturally occurring isoform in an RT-PCR based assay, and demonstrated insensitivity to cisplatin and an ability to support cell growth similar to wild-type controls (Brandao et al., 2011; Bouwman et al., 2013); Observed in individuals with personal and/or family history of breast, ovarian, and other cancers (van Harssel et al., 2010; Brandao et al., 2011; Momozawa et al., 2018; Bakos et al., 2021; Delahunty et al., 2022); Also known as 811C>T; This variant is associated with the following publications: (PMID: 19949876, 29106415, 23867111, 16267036, 23034506, 21638052, 23893897, 25056543, 30287823, 31131967, 31853058, 35464868, 29360161, 33471991, 9582019, 9926942, 9788437, 20215511, 15385441, 32546644, 32467295, 32377563, 29884841, 34130653, 35263119, 34981296) -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 01, 2024	The p.T231M variant (also known as c.692C>T), located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 692. The threonine at codon 231 is replaced by methionine, an amino acid with similar properties. This variant has been reported in individuals undergoing breast cancer risk counseling and genetic testing and in an individual diagnosed with pancreatic cancer (van Harssel JJ et al. Fam. Cancer. 2010 Jun;9:193-201; Michils G et al. J. Mol. Diagn. 2012 Nov;14:623-30; Dudley B et al. Cancer, 2018 04;124:1691-1700). This alteration has been reported with a carrier frequency of 0.00028 in 7051 unselected breast cancer patients and was not identified in 11241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun. 2018 10;9:4083). In one study, RT-PCR analysis revealed partial exon 11 skipping, resulting in the production of full-length transcripts as well as increased expression of two isoforms that are also present in controls (Brandão RD et al. Breast Cancer Res. Treat. 2011 Oct;129:971-82; Ambry internal data). In one cDNA-based functional assay, this alteration was predicted to be neutral (Bouwman P et al. Cancer Discov. 2013 Oct;3:1142-55). In addition, this alteration was classified as uncertain significance based on a multifactorial analysis model of variant classification (Parsons MT et al. Hum. Mutat. 2019 09;40:1557-1578). Of note, this alteration is also designated as 811C>T in some published literature. This amino acid position is poorly 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. -
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	Jan 22, 2017	- -

Breast-ovarian cancer, familial, susceptibility to, 1

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Aug 29, 2017	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Jun 20, 2002	- -

Hereditary breast ovarian cancer syndrome

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	Nov 16, 2021	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Oct 29, 2024

Variant summary: BRCA1 c.692C>T (p.Thr231Met) 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 4.4e-05 in 247512 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome (4.4e-05 vs 0.001), allowing no conclusion about variant significance. c.692C>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and pancreatic cancer (e.g. Judkins_2005, van Harssel_2010, Brandao_2011, Dudley_2018, Momozawa_2018, Dorling_2021, Delahunty_2022, Adamson_2023). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Two independent studies have shown that this variant does not affect the expression level of the full length transcript but gives rise to increased expression of a naturally occurring isoform lacking exon 11, the consequence of which is unknown (Brandao_2011, Tammaro_2014). Using different assays to assess the ability of variants to complement Brca1-deficient mouse embryonic stem cells in homologous recombination DNA repair (HRR), Bouwman et al (2013 and 2020) determined c.692C>T to be neutral. A publication involving the ENIGMA network of collaborators (Parsons_2019) assigned a classification of uncertain significance based on likelihood ratios (LRs) for pathogenicity estimated from clinical data of co-occurrence, family history and bioinformatic predictions. However, Bouwman et al (2020) using multifactorial likelihood analysis from their study combined with Parsons_2019 study determined the variant of interest to have very low posterior probability of being pathogenic. The following publications have been ascertained in the context of this evaluation (PMID: 37460928, 34130653, 23867111, 32546644, 21638052, 35263119, 33471991, 29360161, 16267036, 23034506, 30287823, 31131967, 15385441, 25056543, 19949876). ClinVar contains an entry for this variant (Variation ID: 55669). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Hereditary cancer

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

Sep 11, 2024

This variant is considered likely benign or benign based on one or more of the following: it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease, and/or has normal protein function, and/or has lack of segregation with disease, and/or has been detected in co-occurrence with known pathogenic variant, and/or has lack of disease association in case-control studies, and/or is located in a region inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.031

BayesDel_noAF

Uncertain

0.0

CADD

Benign

DANN

Benign

0.86

DEOGEN2

Benign

0.093

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

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.36

LIST_S2

Uncertain

0.95

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

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.11

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

MetaSVM

Uncertain

-0.073

MutationAssessor

Benign

0.0

N;N;N;.;N;.;.;.;.;.;.;.;.;.

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.18

N;N;N;N;N;N;N;N;N;N;.;N;N;N

REVEL

Uncertain

0.55

Sift

Uncertain

0.0070

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

Sift4G

Uncertain

0.039

D;D;T;D;T;.;.;T;.;D;.;D;.;D

Polyphen

0.66

P;.;.;.;P;.;P;.;.;B;.;.;.;.

Vest4

0.32

MVP

0.57

MPC

0.15

ClinPred

0.023

GERP RS

0.30

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.022

gMVP

0.16

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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