rs80357034

Variant names:

• chr17-43067610-G-A
• rs80357034
• NM_007294.4:c.5072C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-43067610-G-A
• chr17-43067610-G-C
• chr17-43067610-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_007294.4(BRCA1):​c.5072C>T​(p.Thr1691Ile) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1691K) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 30)
• Consequence: BRCA1 NM_007294.4 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10 U:2 O:1
• Conservation: PhyloP100: 6.01

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 16 ACMG points.

• PM1: In a domain BRCT 1 (size 94) in uniprot entity BRCA1_HUMAN there are 74 pathogenic changes around while only 17 benign (81%) 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 chr17-43067610-G-T is described in Lovd as [Likely_pathogenic].
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 17-43067610-G-A is Pathogenic according to our data. Variant chr17-43067610-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 37628.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.5072C>T	p.Thr1691Ile	missense_variant, splice_region_variant	Exon 16 of 23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.5072C>T	p.Thr1691Ile	missense_variant, splice_region_variant	Exon 16 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10 Uncertain:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:2 Uncertain:2 Other:1

Feb 20, 2004

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

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Brotman Baty Institute, University of Washington

Significance: not provided

Review Status: no classification provided

Collection Method: in vitro

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Molecular Endocrinology Laboratory, Christian Medical College

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 06, 2007

Sharing Clinical Reports Project (SCRP)

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

May 14, 2018

Department of Medical Genetics, National Institute of Health

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

We identified the heterozygous variant NM_007294.3:c.5072C>T (p.Thr1691Ile) in BRCA1 gene in a Congolese family with four female cases of breast/ovarian cancer over two generations. This variant has previously been reported six times in families with hereditary breast and ovarian cancer syndrome. To date, there was a conflicting clinical significance of this variant in all databases from "Uncertain significance" in two reports to "likely pathogenic" in four others. This new report should contribute to improving the current pathogenicity ranking of this variant, c.5072C>T. -

not provided Pathogenic:3

Jan 28, 2019

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Nov 29, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA1 c.5072C>T (p.Thr1691Ile) variant has been reported in the published literature in an individual affected with breast and/or ovarian cancer (PMID: 29470806 (2018)). Functional evidence suggests that this variant may impact protein function (PMIDs: 20516115 (2010), 23867111 (2013), 25724305 (2015), 30257991 (2018), 30209399 (2018), 30765603 (2019), and 31843900 (2019)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper BRCA1 mRNA splicing. Based on the available information, this variant is classified as pathogenic. -

Aug 06, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Exonic splice variant demonstrated to disrupt a natural splice donor site, leading to out-of-frame skipping of exon 16 (also known as exon 17 using alternate numbering), as well as a minor amount of normal transcript, as shown via mini-gene assay (PMID: 25724305); Variant classified as non-functional based on a saturation genome editing (SGE) assay measuring cell survival, that accounts for splice impact (PMID: 30209399); Published functional studies measuring protein impact demonstrate a damaging effect: severe folding defect, compromised phosphopeptide selectivity and transcriptional activation, and non-functional homology directed DNA repair (PMID: 20516115, 35665744, 32546644); In silico analysis supports a deleterious effect on splicing; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in a patient with a personal history consistent with pathogenic variants in this gene (PMID: 29470806); Not observed in large population cohorts (gnomAD); Also known as 5191C>T; This variant is associated with the following publications: (PMID: 20516115, 17305420, 23867111, 25782689, 26913838, 28781887, 30209399, 30787465, 35665744, 31447099, 34597585, 30765603, 29470806, 31843900, 25348405, 32546644, 25724305) -

Familial cancer of breast Pathogenic:1

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Hereditary cancer-predisposing syndrome Pathogenic:1

Dec 22, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T1691I pathogenic variant (also known as c.5072C>T), located in coding exon 15 of the BRCA1 gene, results from a C to T substitution at nucleotide position 5072. The threonine at codon 1691 is replaced by isoleucine, an amino acid with similar properties. Multiple RNA studies show that this alteration results in out-of-frame skipping of coding exon 15 (also called Exon 17 in the literature), however this event may be incomplete (Ambry internal data; Ahlborn LB et al. Breast Cancer Res. Treat. 2015 Apr; 150(2):289-98). One downstream functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay and that this event may be, at least in part, due to an RNA defect (Findlay GM et al. Nature. 2018 10;562:217-222). In addition, multiple protein functional assays, including a cell-based transcription activation assay and a homology directed DNA repair assay found that this protein effect was non-functional leading to the possibility of a combined deleterious RNA and protein effect (Lee MS et al. Cancer Res. 2010 Jun; 70(12):4880-90; Petitalot A et al. Mol. Cancer Res. 2019 01;17:54-69). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

BRCA1-related disorder Pathogenic:1

May 31, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRCA1 c.5072C>T variant is predicted to result in the amino acid substitution p.Thr1691Ile. This variant has been reported in individuals with breast and/or ovarian cancer and in a cohort of individuals with breast, ovarian, endometrial, or colon cancer (Table S2, Singh et al. 2018. PubMed ID: 29470806; Tables S6 and S8, Casadei et al. 2019. PubMed ID: 31843900; Caputo et al. 2021. PubMed ID: 34597585). Real time-PCR and in vitro experimental studies suggest this variant impacts mRNA splicing and protein function (see, for example, Ahlborn et al. 2015. PubMed ID: 25724305; Casadei et al. 2019. PubMed ID: 31843900; Supplementary Figure 1a, Lee et al. 2010. PubMed ID: 20516115; Tables 1 and S2, Bouwman et al. 2020. PubMed ID: 32546644). Alternative nucleotide changes affecting the same amino acid (p.Thr1691Lys, p.Thr1691Arg) have been reported in ClinVar as likely pathogenic/pathogenic (see ClinVar IDs:37627, 55373). This variant has not been reported in a large population database, indicating it is rare. In Clinvar, this variant is reported as pathogenic or likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/37628/). This variant is interpreted as pathogenic. -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Oct 04, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1691 of the BRCA1 protein (p.Thr1691Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer, ovarian cancer, pancreatic cancer, and/or prostate cancer (PMID: 29202330, 29470806, 31843900; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as c.5135C>T (p.Thr1712Ile). ClinVar contains an entry for this variant (Variation ID: 37628). An algorithm developed specifically for the BRCA1 gene suggests that this missense change is likely to be deleterious (PMID: 17305420). Experimental studies have shown that this missense change affects BRCA1 function (PMID: 20516115, 28781887, 30209399, 30257991, 30765603). Studies have shown that this missense change alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 25724305, 31843900). For these reasons, this variant has been classified as Pathogenic. -

Hereditary breast ovarian cancer syndrome;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1

Sep 01, 2019

King Laboratory, University of Washington

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	.;T;.;.;T;.;.;.;T;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.84	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.38	D
MutationAssessor	Uncertain	2.8	.;M;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-4.8	D;N;.;D;.;N;D;D;D;D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0020	D;D;.;D;.;D;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D;D;D;.;.;D
Polyphen		0.99, 1.0	.;D;.;.;.;.;.;.;D;.
Vest4		0.85
MVP		0.96
MPC		0.18
ClinPred		0.98	D
GERP RS		5.2
Varity_R		0.92
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.66		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.66		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs80357034; hg19: chr17-41219627;