chr17-43115730-A-T

Variant names:

• chr17-43115730-A-T
• rs80357327
• NM_007294.4:c.130T>A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_007294.4(BRCA1):​c.130T>A​(p.Cys44Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C44F) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:15 U:1 O:1
• Conservation: PhyloP100: 4.03

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a zinc_finger_region RING-type (size 41) in uniprot entity BRCA1_HUMAN there are 65 pathogenic changes around while only 6 benign (92%) in NM_007294.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-43115729-C-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 17-43115730-A-T is Pathogenic according to our data. Variant chr17-43115730-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 54191.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43115730-A-T is described in Lovd as [Pathogenic]. Variant chr17-43115730-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.130T>A	p.Cys44Ser	missense_variant	Exon 3 of 23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.130T>A	p.Cys44Ser	missense_variant	Exon 3 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15 Uncertain:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:7 Uncertain:1 Other:1

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Brotman Baty Institute, University of Washington

Significance: not provided

Review Status: no classification provided

Collection Method: in vitro

- -

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

- -

Aug 26, 2022

BRCAlab, Lund University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 10, 2015

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 = 1 -

Mar 24, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 13, 2016

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 27, 2024

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3; PS3; PP1_Strong; PM2_Supporting -

Jul 22, 2015

Department of Medical Genetics, Oslo University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 23, 2003

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Pathogenic:4

Oct 10, 2019

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect: classified as non-functional based on a saturation genome editing assay assessing ability to support growth, and demonstrated defective homology-directed repair activity and BARD1 binding (Starita 2015, Findlay 2018, Caleca 2019); Multi-factorial studies suggest this variant is associated with breast and ovarian cancer (Lindor 2012); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; No data available from control populations to assess the frequency of this variant; Observed in women with a history of breast and/or ovarian cancer and has been suggested to be a recurrent variant in the Greenlandic population (Borg 2010, Hansen 2010, Sweet 2010, Karami 2013); This variant is associated with the following publications: (PMID: 26295337, 21990134, 18182601, 19543972, 24489791, 20104584, 21520273, 20437199, 24312913, 25525159, 25823446, 30209399, 26833046, 21990165, 29339979, 29446198, 18465347, 30678073, 25348012, 30696104, 33087888) -

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 17, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA1 c.130T>A (p.Cys44Ser) variant has been reported in the published literature in individuals with breast and/or ovarian cancer (PMIDs: 33471991 (2021), 28888541 (2017), 19543972 (2010), 20104584 (2010), 20437199 (2010), 18182601 (2008)), and observed in screening studies of individuals with BRCA1 and BRCA2 pathogenic variants (PMIDs: 29339979 (2018), 29446198 (2018)). Functional studies indicate this variant has deleterious effects on BRCA1 protein function and DNA damage repair-associated cell survival (PMIDs: 30209399 (2018), 25823446 (2015)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Aug 03, 2020

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces cysteine with serine at codon 44 in the RING domain of the BRCA1 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >=0.7, PMID: 27666373). The variant protein has been shown to be functionally defective in a haploid cell proliferation assay (PMID 30209399). This variant has been reported in individuals affected with breast cancer (PMID: 19543972, 20104584) and ovarian cancer (PMID: 20437199). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different missense variants affecting the same codon, p.Cys44Tyr and p.Cys44Phe, are known to be pathogenic (Clinvar variation ID: 54199, 54200), indicating that cysteine at this position is important for BRCA1 function. Based on the available evidence, this variant is classified as Pathogenic. -

Mar 15, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.C44S pathogenic mutation (also known as c.130T>A), located in coding exon 2 of the BRCA1 gene, results from a T to A substitution at nucleotide position 130. The cysteine at codon 44 is replaced by serine, an amino acid with dissimilar properties. This alteration occurs in the functionally important RING finger domain (Abkevich V et al. J. Med. Genet. 2004 Jul;41:492-507). This alteration has been reported in multiple individuals diagnosed with breast and/or ovarian cancer (Begg CB et al, JAMA 2008 Jan; 299(2):194-201; Hansen TV et al, Breast Cancer Res. Treat. 2010 Nov; 124(1):259-64; Sweet K et al, Breast Cancer Res. Treat. 2010 Feb; 119(3):737-43; Capanu M et al, Genet. Epidemiol. 2011 Jul; 35(5):389-97). One functional study found that this nucleotide substitution is non-functional in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 Oct;562:217-222). Two other alterations at the same codon, p.C44Y (c.131G>A) and p.C44F (c.131G>T), have been identified in multiple breast and/or ovarian cancer families (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). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Hereditary breast ovarian cancer syndrome Pathogenic:2

Jun 09, 2017

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The BRCA1 c.130T>A (p.Cys44Ser) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution at a highly conserved cysteine residue in the RING finger domain (InterPro). 5/5 in silico tools predict a damaging outcome for this variant. This variant is absent from the large control database ExAC and control cohorts reported in the literature (0/112062 control chromosomes). The variant has been identified in numerous HBOC patient. Several overlapping variants are present in HGMD (Cys44Arg, Cys44Gly, Cys44Phe, and Cys44Tyr), suggesting a mutational hotspot that is critical for protein function. In addition, this variant C44S has been functionally tested and shown to disrupt BARD1 binding, and impairs ubiquitin ligase activity and homolgy-directed repair (Starita_2015). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

May 25, 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 serine, which is neutral and polar, at codon 44 of the BRCA1 protein (p.Cys44Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and ovarian cancer (PMID: 18182601, 18500671, 19543972, 20104584, 20437199). ClinVar contains an entry for this variant (Variation ID: 54191). Advanced modeling performed at Invitae incorporating data from internal and/or published 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, 20029420, 25652403). 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: 16403807, 20103620, 21725363, 21922593, 21990134, 23161852, 27272900). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.47	.;T;.;.;.;D;.;T;T;.;T;D;.
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D;D;T;D;D;T
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H;H;H;H;H;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.4	N;N;N;N;N;D;N;.;N;N;N;D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;.;D;D;D;D;D
Sift4G	Benign	0.13	T;D;D;T;T;.;D;.;D;.;D;.;.
Polyphen		0.98, 1.0, 1.0	.;D;.;.;D;.;D;.;.;.;.;.;.
Vest4		0.93
MutPred		0.98		Gain of disorder (P = 0.0935);Gain of disorder (P = 0.0935);Gain of disorder (P = 0.0935);Gain of disorder (P = 0.0935);Gain of disorder (P = 0.0935);Gain of disorder (P = 0.0935);Gain of disorder (P = 0.0935);Gain of disorder (P = 0.0935);Gain of disorder (P = 0.0935);Gain of disorder (P = 0.0935);Gain of disorder (P = 0.0935);Gain of disorder (P = 0.0935);Gain of disorder (P = 0.0935);
MVP		1.0
MPC		0.41
ClinPred		1.0	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.89

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

Other links and lift over

dbSNP: rs80357327; hg19: chr17-41267747;