rs80357446

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001407841.1(BRCA1):c.-8+1G>T variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,168 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

BRCA1
NM_001407841.1 splice_donor, intron

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:23U:1O:1

Conservation

PhyloP100: 3.48

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 Pathogenic. Variant got 18 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 10, offset of 4, new splice context is: caaGTaagt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-43115729-C-A is Pathogenic according to our data. Variant chr17-43115729-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 54200.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43115729-C-A is described in Lovd as [Pathogenic]. Variant chr17-43115729-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4 link	c.131G>T	p.Cys44Phe	missense_variant	Exon 3 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.131G>T	p.Cys44Phe	missense_variant	Exon 3 of 23	1	NM_007294.4	ENSP00000350283.3		P38398-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461168

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726864

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:23Uncertain:1Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1

Pathogenic:8Uncertain:1Other:1

Feb 20, 2004

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 08, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces cysteine with phenylalanine at codon 44 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have reported that this variant impacts BRCA1 function in homology-directed repair, ubiquitin E3 ligase, BARD1 binding, haploid cell proliferation and protein folding assays (PMID: 11573085, 20103620, 23161852, 25823446, 30209399; DOI:10.1158/2767-9764.CRC-21-0064). This variant has been reported in at least six individuals affected with breast and ovarian cancer (PMID: 16912212, 18159056, 22711857, 22713736, 28486781) and multiple suspected hereditary breast and ovarian cancer families (PMID: 12048272, 16267036, 19241424). This variant is also reported to have segregation and tumor pathology likelihood ratios for pathogenicity of 156.1745 and 41.2405, respectively (PMID: 31131967). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Apr 21, 2016

Michigan Medical Genetics Laboratories, University of Michigan

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 26, 2022

BRCAlab, Lund University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 07, 2012

Sharing Clinical Reports Project (SCRP)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 02, 2015

Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2017

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Brotman Baty Institute, University of Washington

Significance: not provided

Review Status: no classification provided

Collection Method: in vitro

- -

May 05, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

A known pathogenic variant was detected in the BRCA1 gene in this specimen. This sequence change replaces cysteine with phenylalanine at codon 44 of the BRCA1 protein (p.Cys44Phe). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and phenylalanine. This variant is not found in gnomAD exomes. This variant has been reported in individuals affected with breast and or ovarian cancer (PMID: 23633455, 18159056, 25777348, 16267036). This variant is also known as 250G>T in the literature. ClinVar contains an entry for this variant (Variation ID: 54200) and classifies this variant as Pathogenic, rated 3 stars, reviewed by expert panel. Experimental studies have shown that this missense change disrupts several BRCA1 protein functions, including single-strand annealing and homology directed repair, regulation of centrosome duplication, BARD1 binding and ubiquitin ligase activity (PMID: 20103620, 16403807, 23161852, 21725363, 27272900). Therefore, this variant has been classified as pathogenic. -

Jun 18, 2019

Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 0.999964 -

not provided

Pathogenic:7

Nov 18, 2014

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2020

GeneKor MSA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is a single amino acid change from Cysteine to Phenylalanine at amino acid residue 44 of the BRCA1 protein. The Cysteine residue is highly conserved among species and is located in a functional domain of the protein and a region known to interact with multiple proteins. There is a large physiochemical difference between Cysteine acid and Phenylalanine (Grantham Score 205). To our knowledge, this variant is not present in population databases (rs80357446). This variant is also known as c.250G>T in the literature and it was shown to disrupt normal protein function by a yeast two-hybrid E3 Ub-ligase activity assay, a homology directed recombination assay, a BARD1 binding assay and a centrosome amplification assay (PMID: 20103620, 21725363). In addition, several individuals with personal and/or family history consistent with Hereditary Breast and Ovarian Cancer syndrome were found to carry this variant (PMID: 22713736). Algorithms developed to predict the effect of missense changes on protein structure and function suggest that this variant may be damaging to the protein. The mutation database Clinvar contains entries for this variant (Variation ID: 54200). -

Sep 11, 2019

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 06, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect: disrupted homology-directed repair and BARD1 binding, and loss of E3 ubiquitin ligase activity and centrosome amplification (Morris 2006, Ransburgh 2010, Kais 2012, Starita 2015, Findlay 2018); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (John 2007, Hall 2009, Jalkh 2012, Lolas Hamameh 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Multifactorial likelihood analysis suggests this variant is pathogenic (Parsons 2019); Also known as 250G>T; This variant is associated with the following publications: (PMID: 24312913, 26187060, 23161852, 16403807, 25823446, 28486781, 30350268, 15235020, 20103620, 11320250, 22713736, 12732733, 21725363, 23633455, 25085752, 25777348, 25814778, 18159056, 19241424, 27272900, 28202063, 28364669, 29446198, 30209399, 33087888, 31131967, 24389207, 20104584, 8944023) -

Dec 14, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 17, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome

Pathogenic:3

Mar 07, 2018

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRCA1 c.131G>T (p.Cys44Phe) results in a non-conservative amino acid change located in the RING binding domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 245760 control chromosomes (gnomAD). The variant, c.131G>T, has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Alsop_2012, Jalkh_2012, El Saghir_2015, Christie_2017, etc). These data indicate that the variant is very likely to be associated with disease. Multiple functional studies found that the variant significantly impacts proper BRCA1 protein function (Kais_2012, Morris_2006,Ransburgh_2010, Towler_2013, and Thouvenot_2016). Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "likely pathogenic/pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic. -

Sep 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 44 of the BRCA1 protein (p.Cys44Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and or ovarian cancer (PMID: 16267036, 18159056, 23633455, 25777348). This variant is also known as 250G>T. ClinVar contains an entry for this variant (Variation ID: 54200). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 12732733, 16403807, 20103620, 21725363, 22843421, 23161852, 27272900). This variant disrupts the p.Cys44 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19543972, 21922593, 25823446, 27083775). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Dec 17, 2015

Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Breast and/or ovarian cancer

Pathogenic:2

Nov 10, 2011

Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 17, 2022

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Dec 27, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.C44F pathogenic mutation (also known as c.131G>T), located in coding exon 2 of the BRCA1 gene, results from a G to T substitution at nucleotide position 131. The cysteine at codon 44 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This mutation occurs in the functionally important RING finger domain (Abkevich V et al. J. Med. Genet. 2004 Jul;41:492-507). Based on internal structural assessment, this alteration is predicted to disrupt formation of zinc binding site 1 and overall folding of the BRCA1 protein. This is consistent with Brzovic PS et al (2010), who showed that experimentally altering ligands at this residue yields BRCA1 RING domains that fail to fold properly (Brzovic PS et al. Nat. Struct. Biol. 2001 Oct;8:833-7). Multiple functional studies have shown that this alteration is deleterious including a centrosome amplification assay, a homology directed repair assay, a single stranded annealing assay and a high throughput cell survival assay (Kais Z et al. Oncogene. 2012 Feb;31:799-804; Ransburgh DJ et al. Cancer Res. 2010 Feb;70:988-95; Towler WI et al. Hum. Mutat. 2013 Mar;34:439-45; Findlay GM et al. Nature, 2018 Sep;). This mutation has been identified in multiple breast and/or ovarian cancer families in the literature (Alsop K et al. J. Clin. Oncol. 2012 Jul;30:2654-63; Jalkh N et al. Hered Cancer Clin Pract. 2012 Jun;10:7; George J et al. Clin. Cancer. Res. 2013 Jul;19:3474-84; Lolas Hamameh S et al. Int. J. Cancer. 2017 Aug;141:750-756). In addition, two other alterations at the same codon, p.C44Y and p.C44S, have been classified as definitely pathogenic (p>0.99) by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, and mutation co-occurrence (Easton DF et al. Am. J. Hum. Genet. 2007 Nov;81:873-83; Lindor NM et al. Hum. Mutat. 2012 Jan;33:8-21; Vallee MP et al. Hum. Mutat. 2012 Jan;33:22-8). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as a pathogenic mutation. -

Apr 11, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S

Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.47

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

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.95

D;D;D;D;D;D;D;D;D;T;D;D;T

M_CAP

Pathogenic

0.77

MetaRNN

Pathogenic

0.99

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.3

H;H;H;H;H;.;.;.;.;.;.;.;.

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-3.2

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

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

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

Sift4G

Uncertain

0.018

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

Polyphen

0.99, 0.97, 1.0

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

Vest4

0.87

MutPred

0.98

Loss of disorder (P = 0.0952);Loss of disorder (P = 0.0952);Loss of disorder (P = 0.0952);Loss of disorder (P = 0.0952);Loss of disorder (P = 0.0952);Loss of disorder (P = 0.0952);Loss of disorder (P = 0.0952);Loss of disorder (P = 0.0952);Loss of disorder (P = 0.0952);Loss of disorder (P = 0.0952);Loss of disorder (P = 0.0952);Loss of disorder (P = 0.0952);Loss of disorder (P = 0.0952);

MVP

1.0

MPC

0.15

ClinPred

0.99

GERP RS

6.0

Varity_R

0.98

gMVP

0.90

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