rs80357234

Positions:

• chr17-43104949-G-A
• chr17-43104949-G-C
• chr17-43104949-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_007294.4(BRCA1):​c.220C>T​(p.Gln74Ter) variant causes a stop gained 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 (★★★). Synonymous variant affecting the same amino acid position (i.e. Q74Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:16 O:1
• Conservation: PhyloP100: 4.09

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-43104949-G-A is Pathogenic according to our data. Variant chr17-43104949-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 54499.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43104949-G-A is described in Lovd as [Pathogenic]. Variant chr17-43104949-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.220C>T	p.Gln74Ter	stop_gained	5/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.220C>T	p.Gln74Ter	stop_gained	5/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:7 Other:1

Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -
not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -
Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Sep 08, 2016	Variant allele predicted to encode a truncated non-functional protein. -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Endocrinology Laboratory, Christian Medical College	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	May 27, 2024	PVS1; PM2_supporting; PM5_PTC_Strong -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 11, 2023	- -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2017	This variant is denoted BRCA1 c.220C>T at the cDNA level and p.Gln74Ter (Q74X) at the protein level. Using alternate nomenclature, this variant has been published as BRCA1 339C>T. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAA>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in individuals with hereditary breast and ovarian cancer (Stoppa-Lyonnet 1997, Kiechle 2000, Kwong 2016) and is considered pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Aug 13, 2018	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Hereditary breast ovarian cancer syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 17, 2024	This sequence change creates a premature translational stop signal (p.Gln74*) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast or ovarian cancer (PMID: 9150149). ClinVar contains an entry for this variant (Variation ID: 54499). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Jan 31, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 24, 2017	Variant summary: The BRCA1 c.220C>T (p.Gln74X) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Tyr101X, p.Glu143X, p.Ser157X, etc.). This variant is absent in 121250 control chromosomes from ExAC. This variant has been reported in several HBOC affected patients in literature (Stoppa-Lyonnet_1997, Kiechle_2000, Lecarpentier_2012, Bjorkman_2015, Wang_2015, Kwong_2016, Tung_2016, Lang_2017) and clinical databases (UMD, ClinVar). In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

Ovarian cancer Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

3DMed Clinical Laboratory Inc

Oct 23, 2017

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 28, 2022

The p.Q74* pathogenic mutation (also known as c.220C>T), located in coding exon 4 of the BRCA1 gene, results from a C to T substitution at nucleotide position 220. This changes the amino acid from a glutamine to a stop codon within coding exon 4. This mutation has been previously reported in high-risk breast and/or ovarian cancer cohorts (Stoppa-Lyonnet D et al. Am. J. Hum. Genet., 1997 May;60:1021-30; Tung N et al. J. Clin. Oncol., 2016 May;34:1460-8; Sun J et al. Clin. Cancer Res. 2017 Oct;23(20):6113-6119; Singh et al. Breast Cancer Res. Treat. 2018 Jul;170(1):189-196 ). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.91	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A;D;D;D;D
Vest4		0.88
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.35		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.35		Position offset: 7

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

Publications

LitVar

Other links and lift over

dbSNP: rs80357234; hg19: chr17-41256966;