17-43115750-G-T

Position:

• chr17-43115750-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_007294.4(BRCA1):​c.110C>A​(p.Thr37Lys) 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 (★★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:5 U:1 O:1
• Conservation: PhyloP100: 4.40

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]

BRCA1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98
• PP5: Variant 17-43115750-G-T is Pathogenic according to our data. Variant chr17-43115750-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 54131.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43115750-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.110C>A	p.Thr37Lys	missense_variant	3/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.110C>A	p.Thr37Lys	missense_variant	3/23	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:5 Uncertain:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

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

not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 19, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Jul 19, 2006	- -
Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Aug 10, 2015	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 -

Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 20, 2022

The p.T37K pathogenic mutation (also known as c.110C>A), located in coding exon 2 of the BRCA1 gene, results from a C to A substitution at nucleotide position 110. The threonine at codon 37 is replaced by lysine, an amino acid with similar properties. This alteration was identified in a Malaysian woman diagnosed with triple-negative breast cancer at age 31, as well as an African America woman diagnosed with bilateral breast cancer, at ages 27 and 33 (Yang XR et al. Breast Cancer Res Treat. 2017 Oct;165:687-697; Skendelas JP et al. Clin Case Rep. 2018 Dec;6:2457-2462). 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 10;562:217-222). Another alteration at the same codon, p.T37R (c.110C>G), has also been determined to be functionally and structurally deleterious (Findlay GM et al. Nature. 2018 10;562:217-222; Morris JR et al. Hum Mol Genet. 2006; 15:599-606; Ransburgh DJ et al. Cancer Res. 2010; 70:988-95; Towler WI et al. Hum Mutat. 2013; Ruffner H et al. Proc. Natl. Acad. Sci. U.S.A. 2001 Apr; 98(9):5134-9; Zhu Q et al. Nature 2011 Sep; 477(7363):179-84; Brzovic PS et al. Nat. Struct. Biol. 2001 Oct;8(10):833-7; Ambry Internal Data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 18, 2022

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. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 25823446, 27272900, 30209399). Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is expected to disrupt BRCA1 protein function. This missense change has been observed in individual(s) with breast cancer (PMID: 19543972, 25823446, 28664506, 30564348). ClinVar contains an entry for this variant (Variation ID: 54131). This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 37 of the BRCA1 protein (p.Thr37Lys). This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.44	.;T;.;.;.;D;.;T;T;.;T;D;.
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.5	M;M;M;M;M;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.80	N;N;N;N;N;D;N;.;N;N;N;D;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;.;D;D;D;D;D
Sift4G	Uncertain	0.025	D;D;D;D;D;.;D;.;D;.;D;.;.
Polyphen		0.98, 1.0	.;D;.;.;D;.;D;.;.;.;.;.;.
Vest4		0.91
MutPred		0.94		Gain of methylation at T37 (P = 0.0325);Gain of methylation at T37 (P = 0.0325);Gain of methylation at T37 (P = 0.0325);Gain of methylation at T37 (P = 0.0325);Gain of methylation at T37 (P = 0.0325);Gain of methylation at T37 (P = 0.0325);Gain of methylation at T37 (P = 0.0325);Gain of methylation at T37 (P = 0.0325);Gain of methylation at T37 (P = 0.0325);Gain of methylation at T37 (P = 0.0325);Gain of methylation at T37 (P = 0.0325);Gain of methylation at T37 (P = 0.0325);Gain of methylation at T37 (P = 0.0325);
MVP		0.98
MPC		0.48
ClinPred		0.99	D
GERP RS		6.0
Varity_R		0.96
gMVP		0.88

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: rs80356880; hg19: chr17-41267767;