rs80357034

chr17-43067610-G-Achr17-43067610-G-Cchr17-43067610-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. T1691A) has been classified as Uncertain significance.

• 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 hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 7 benign, 17 uncertain 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 ClinVar as [Likely_pathogenic]. Clinvar id is 37627.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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/exons	MANE	UniProt
BRCA1	NM_007294.4	c.5072C>T	p.Thr1691Ile	missense_variant, splice_region_variant	16/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.5072C>T	p.Thr1691Ile	missense_variant, splice_region_variant	16/23	1	NM_007294.4	P4

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

Uncertain significance, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Mar 06, 2007	- -
Pathogenic, no assertion criteria provided	clinical testing	Department of Medical Genetics, National Institute of Health	May 14, 2018	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. -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Feb 20, 2004	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Endocrinology Laboratory, Christian Medical College	-	- -
not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -

not provided Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 11, 2019	Published functional studies demonstrate a damaging effect: Disrupts a natural splice donor site and causes abnormal splicing, leading to out-of-frame skipping of exon 16 (also known as exon 17 using alternate numbering) as shown via mini-gene assay; At the protein level, demonstrates severe folding defect and compromised phosphopeptide selectivity and transcriptional activation (Lee 2010, Ahlborn 2015); Not observed in large population cohorts (Lek 2016); Also known as BRCA1 5191C>T; Protein-based in silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. In addition, multiple splicing models predict that this variant may destroy the nearby natural splice site. However, in the absence of RNA or functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 20516115, 25724305, 17305420, 23867111, 25782689, 26913838, 28781887, 30209399, 29470806, 30765603, 31447099) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 29, 2021	In the published literature, this variant has been reported in an individual affected with breast and/or ovarian cancer (PMID: 29470806 (2018)). In addition, this variant is reported to perturb normal mRNA splicing and affect BRCA1 transcriptional activity, growth complementation, peptide binding specificity, protein folding, and homologous repair activity based on experimental evidence (PMIDs: 20516115 (2010), 23867111 (2013), 25724305 (2015), 30257991 (2018), 30765603 (2019), and 31843900 (2019)). Furthermore, one study showed this variant apparently lost functional activity in a large-scale study using a haploid cell line (PMID: 30209399 (2018)). This variant has not been reported in large, multi-ethnic general populations. Variant is predicted to have a damaging effect on the protein and located in potentially critical domain of the protein.Therefore, we predict that the variant is likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 28, 2019	- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 22, 2021

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

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 25, 2023

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, enodmetrial, 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.Thr1691Ala, p.Thr1691Lys, p.Thr1691Arg, p.Thr1691Thr) have been reported in individuals with breast and/or ovarian cancer (Human Gene Mutation Database, http://www.hgmd.cf.ac.uk/ac/index.php). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating it is rare. In Clinvar, this variant is reported as pathogenic or likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/37628/). In summary, the c.5072C>T (p.Thr1691Ile) variant is interpreted as pathogenic. -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 04, 2023

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

Pathogenic, no assertion criteria provided

research

King Laboratory, University of Washington

Sep 01, 2019

- -

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
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
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D
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;