rs397509338

Positions:

• chr17-43094603-G-A

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.928C>T​(p.Gln310Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BRCA1 NM_007294.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:10
• Conservation: PhyloP100: 1.74

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 17-43094603-G-A is Pathogenic according to our data. Variant chr17-43094603-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 55758.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43094603-G-A is described in Lovd as [Pathogenic]. Variant chr17-43094603-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.928C>T	p.Gln310Ter	stop_gained	10/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.928C>T	p.Gln310Ter	stop_gained	10/23	1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461866 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -
Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Oct 18, 2016	Variant allele predicted to encode a truncated non-functional protein. -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Aug 26, 2022	- -

Hereditary breast ovarian cancer syndrome Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Veritas Genetics, Veritas Genetics	Jun 28, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 04, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 55758). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 11059339, 17100994, 22798144, 29020732). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln310*) 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). -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 07, 2019	Variant summary: BRCA1 c.928C>T (p.Gln310X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the 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. The variant was absent in 251376 control chromosomes (gnomAD). c.928C>T has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. A database, UMD, reports the variant to co-occur with another pathogenic BRCA1 variant, c.2433delC (p.Lys812ArgfsX3). Four ClinVar submissions including an expert panel, ENIGMA (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 22, 2015	This variant is denoted BRCA1 c.928C>T at the cDNA level and p.Gln310Ter (Q310X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAG>TAG) , and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant, also published as BRCA1 c.1047C>T using alternate nomenclature, has been reported in association with breast and ovarian cancer (Wang 2000, Kim 2006, Seong 2009, Tang 2001), and is considered pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 06, 2023	This variant changes 1 nucleotide in exon 10 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in multiple individuals affected with breast and/or ovarian cancer (PMID: 11059339, 11433401, 17100994, 22438049, 22798144, 29020732, 30982232, 30350268, 30309222, 31958182) and has been detected in a breast cancer case-control meta-analysis in 3/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_001915). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 23, 2021	The p.Q310* pathogenic mutation (also known as c.928C>T), located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 928. This changes the amino acid from a glutamine to a stop codon within coding exon 9. This mutation has been detected in multiple breast and/or ovarian cancer patients (Wang PH et al. Jpn J Clin Oncol, 2000 Aug;30:343-8; Seong MW et al. Clin Genet, 2009 Aug;76:152-60; Meisel C et al. Arch Gynecol Obstet, 2017 May;295:1227-1238; Eoh KJ et al. Cancer Res Treat, 2018 Jul;50:917-925; Ryu JM et al. Breast Cancer Res Treat, 2019 Jan;173:385-395; Wang J et al. Cancer Med, 2019 05;8:2074-2084; Choi MC et al. Cancer Res Treat, 2020 Apr;52:634-644; Chao A et al. J Gynecol Oncol, 2020 May;31:e24; Dorling et al. N Engl J Med. 2021 02;384:428-439). This alteration was also identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620). Of note, this alteration is also designated as 1047C>T and 1047 (CAG to TAG) in published literature. In addition to the clinical data presented in the literature, 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	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.77	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;D;D;D;D;D;D;D;D
Vest4		0.86
GERP RS		3.9

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: rs397509338; hg19: chr17-41246620;