rs80357498

Variant names:

• chr17-43115744-C-A
• rs80357498
• NM_007294.4:c.116G>T

Your query was ambiguous. Multiple possible variants found:

• chr17-43115744-C-A
• chr17-43115744-C-G
• chr17-43115744-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_001407694.1(BRCA1):​c.-142G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_001407694.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 3.48

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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 17-43115744-C-A is Pathogenic according to our data. Variant chr17-43115744-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 37393.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-43115744-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.116G>T	p.Cys39Phe	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.116G>T	p.Cys39Phe	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/Likely pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:3 Other:1

-

Brotman Baty Institute, University of Washington

Significance: not provided

Review Status: no classification provided

Collection Method: in vitro

- -

Dec 20, 2010

Sharing Clinical Reports Project (SCRP)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 02, 2020

BRCAlab, Lund University

Significance: Likely 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

- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Jul 05, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.C39F variant (also known as c.116G>T), located in coding exon 2 of the BRCA1 gene, results from a G to T substitution at nucleotide position 116. The cysteine at codon 39 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This alteration was identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620). This nucleotide substitution was non-functional in a high-throughput, genome editing, haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222), and demonstrated impaired BARD1 binding and E3 Ubiquitin Ligase activity (Starita LM et al. Genetics, 2015 Jun;200:413-22). Additionally, codon 39 is located in a critical region of the BRCA1 protein RING domain. Multiple alterations at this codon, including p.C39R, p.C39Y, and p.C39S have been shown to alter the structure of the RING domain and negatively impact protein function and binding (Ruffner H et al. Proc Natl Acad Sci U S A. 2001 Apr 24;98(9):5134-9; Brzovic PS et al. Proc Natl Acad Sci USA. 2003 May;100(10):5646-51; Ransburgh DJ et al. Cancer Res. 2010 Feb 1;70(3):988-95; Sweet K et al. Breast Cancer Res Treat. 2010 Feb;119(3):737-43). 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. -

Mar 07, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces cysteine with phenylalanine at codon 39 in the RING domain 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 shown that this mutant protein has decreased ubiquitin protein ligase activity and is deficient in BARD1 binding, and is predicted to be non-functional for homology-directed DNA repair (PMID: 25823446, 30219179). This variant has been reported to be loss-of-function in a haploid cell proliferation assay (PMID: 30209399). This variant has been reported in individuals affected with breast cancer (PMID: 33278427), and has been identified in one family among the CIMBA participants (PMID: 29446198) (https://cimba.ccge.medschl.cam.ac.uk/). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon, c.115T>A (p.Cys39Ser), c.115T>C (p.Cys39Arg), c.115T>G (p.Cys39Gly), c.116G>A (p.Cys39Tyr), and c.117T>G (p.Cys39Trp) are considered to be disease-causing (ClinVar variation ID: 54151, 54152, 54153, 37392, 267497), supporting that the cysteine at this position is important for protein function. Based on the available evidence, this variant is classified as Pathogenic. -

Breast and/or ovarian cancer Pathogenic:1

Jan 12, 2022

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Aug 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely 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 39 of the BRCA1 protein (p.Cys39Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer and/or ovarian cancer (PMID: 28888541, 29446198, 33278427). ClinVar contains an entry for this variant (Variation ID: 37393). 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: 30209399). This variant disrupts the p.Cys39 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9808526, 11320250, 12827452, 19543972, 21725363, 21922593, 21990134, 22843421, 23161852, 24489791). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.47	.;T;.;.;.;D;.;T;T;.;T;D;.
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	4.4	H;H;H;H;H;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-2.2	N;N;N;D;N;D;N;.;N;N;D;D;D
REVEL	Pathogenic	0.94
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		1.0, 1.0	.;D;.;.;D;.;D;.;.;.;.;.;.
Vest4		0.87
MutPred		0.99		Loss of catalytic residue at H41 (P = 0.107);Loss of catalytic residue at H41 (P = 0.107);Loss of catalytic residue at H41 (P = 0.107);Loss of catalytic residue at H41 (P = 0.107);Loss of catalytic residue at H41 (P = 0.107);Loss of catalytic residue at H41 (P = 0.107);Loss of catalytic residue at H41 (P = 0.107);Loss of catalytic residue at H41 (P = 0.107);Loss of catalytic residue at H41 (P = 0.107);Loss of catalytic residue at H41 (P = 0.107);Loss of catalytic residue at H41 (P = 0.107);Loss of catalytic residue at H41 (P = 0.107);Loss of catalytic residue at H41 (P = 0.107);
MVP		1.0
MPC		0.55
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.99
gMVP		0.92

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: rs80357498; hg19: chr17-41267761;