17-43067610-G-T

Variant names:

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

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_007294.4(BRCA1):​c.5072C>A​(p.Thr1691Lys) 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. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T1691T) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 30)
• Consequence: BRCA1 NM_007294.4 missense, splice_region
• Scores: Splicing: ADA: 0.9266
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 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 14 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.868
• PP5: Variant 17-43067610-G-T is Pathogenic according to our data. 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. Variant chr17-43067610-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.5072C>A	p.Thr1691Lys	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>A	p.Thr1691Lys	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:6 Uncertain:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Dec 12, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 25, 2004

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Brotman Baty Institute, University of Washington

Significance: not provided

Review Status: no classification provided

Collection Method: in vitro

- -

Nov 20, 2008

Sharing Clinical Reports Project (SCRP)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:2

May 07, 2021

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces threonine with lysine at codon 1691 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 transcription activation, haploid cell proliferation, yeast growth inhibition, protease sensitivity, peptide binding and subcellular localization assays (PMID: 20516115, 22277901, 27802165, 28781887, 28961279, 30209399). This variant has been reported in at least six individuals affected with breast and ovarian cancer (PMID: 22277901, 26221963, 26757417, 28188963, 33471991; Leiden Open Variation Database DB-ID BRCA1_000510; Color internal data). 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. -

Feb 01, 2023

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T1691K variant (also known as c.5072C>A), located in coding exon 15 of the BRCA1 gene, results from a C to A substitution at nucleotide position 5072. The threonine at codon 1691 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in multiple individuals with personal and/or family history consistent with hereditary breast and ovarian cancer (HBOC) syndrome (Kuo WH et al. J. Hum. Genet., 2012 Feb;57:130-8; Wong ES et al. PLoS ONE, 2015 Jul;10:e0134408; Ng PS et al. Clin. Genet., 2016 Oct;90:315-23). Functional data show that this alteration is defective in many assays including two transcription activation assays, a protein binding assay, a binding specificity assay and a homology-directed repair assay (Lee MS et al. Cancer Res., 2010 Jun;70:4880-90; Kuo WH et al. J. Hum. Genet., 2012 Feb;57:130-8; Woods NT et al. NPJ Genom Med, 2016 Mar;1; Ambry internal data). Based on published literature and internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Ambry internal data; Williams RS et al. Nat. Struct. Biol., 2001 Oct;8:838-42; Thouvenot P et al. J. Cell. Sci., 2016 12;129:4366-4378). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

not provided Pathogenic:1

Nov 02, 2018

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is denoted BRCA1 c.5072C>A at the cDNA level, p.Thr1691Lys (T1691K) at the protein level, and results in the change of a Threonine to a Lysine (ACA>AAA). Using alternate nomenclature, this variant has been previously published as BRCA1 5191C>A. This variant was observed in several women with breast and/or ovarian cancer (Lin 2011, Kuo 2012, Wong 2015, Ng 2016, Chirasophon 2017). In addition, multiple functional studies have demonstrated this variant to have a severe impact on transactivation, protease sensitivity, binding activity and sensitivity, nuclear spot formation, decreased nuclear localization and absence of growth inhibition (Lee 2010, Kuo 2012, Thouvenot 2016, Woods 2016). BRCA1 Thr1691Lys was not observed in large population cohorts (Lek 2016). This variant is located in the BRCT1 domain and within a region known to interact with multiple other proteins (Paul 2014, UniProt). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider BRCA1 Thr1691Lys to be a likely pathogenic variant. -

Familial cancer of breast Pathogenic:1

-

Center for Precision Medicine, Meizhou People's Hospital

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Sep 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 1691 of the BRCA1 protein (p.Thr1691Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 22277901, 26757417, 29263802, 29752822, 32072338, 32091409). This variant is also known as 5191C>A. ClinVar contains an entry for this variant (Variation ID: 37627). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 20516115, 22277901, 28781887, 30209399). 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	0.94
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	.;T;.;.;T;.;.;.;T;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.33	D
MutationAssessor	Pathogenic	3.2	.;M;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-4.7	D;N;.;D;.;N;D;D;N;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0010	D;D;.;D;.;D;D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;T;D;D;.;.;D
Polyphen		0.89, 1.0	.;P;.;.;.;.;.;.;D;.
Vest4		0.94
MVP		0.95
MPC		0.14
ClinPred		0.98	D
GERP RS		5.2
Varity_R		0.94
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.93
dbscSNV1_RF	Pathogenic	0.78
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: rs80357034; hg19: chr17-41219627;