17-43076488-C-T

Position:

• chr17-43076488-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_007294.4(BRCA1):​c.4484G>A​(p.Arg1495Lys) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 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. R1495M) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: BRCA1 NM_007294.4 missense, splice_region
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13 U:4
• Conservation: PhyloP100: 3.88

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.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-43076488-C-A is described in Lovd as [Pathogenic].
• 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 17-43076488-C-T is Pathogenic according to our data. Variant chr17-43076488-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 37597.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-43076488-C-T is described in Lovd as [Pathogenic]. Variant chr17-43076488-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.4484G>A	p.Arg1495Lys	missense_variant, splice_region_variant	13/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.4484G>A	p.Arg1495Lys	missense_variant, splice_region_variant	13/23	1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13 Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:6 Uncertain:1

Uncertain significance, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Aug 12, 2008	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Dec 10, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 24, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Medical Genetics, Oslo University Hospital	Oct 09, 2015	- -
Likely pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
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, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Nov 25, 2004	- -

not provided Pathogenic:2 Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 09, 2023	RNA analyses demonstrate that this variant leads to skipping of exon 14, resulting in premature protein truncation, subject to nonsense-mediated decay (Houdayer et al., 2012; Wangensteen et al., 2019); Observed in individuals with breast and/or ovarian cancer (Alsop et al., 2012, George et al., 2013, Fernandes et al., 2016, Turner et al., 2018, Slavin et al., 2019); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 4603G>A; This variant is associated with the following publications: (PMID: 22711857, 27741520, 28888541, 22762150, 19471317, 23633455, 22045683, 21523855, 15280182, 16267036, 28637432, 29339979, 28781887, 30728895, 29875428, 29446198, 30765603, 31143303, 31131967, 31911673, 31124283, Tan2020[Abstract], Lertwilaiwittaya2020[Case Report], 34981296, 35918668, 35665744, 15343273, 22737296, 22505045) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 09, 2022	The variant occurs at the last base of an exon and interferes with normal BRCA1 mRNA splicing. It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals affected with breast/ovarian cancer (PMID: 22711857 (2012), 23633455 (2013), 27741520 (2016), 28637432 (2017), 29875428 (2018), 34196900 (2021)). In vitro studies have shown that this variant causes a severe and complete splicing defect resulting in exon 13 (legacy exon 14) skipping (PMID: 19471317 (2009), 22505045 (2012), 31143303 (2019)). Based on the available information, this variant is classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 05, 2021	This missense variant replaces arginine with lysine at codon 1495 of the BRCA1 protein and alters the conserved guanine nucleotide immediately adjacent to the intron 13 splice donor site. RNA studies have shown that this variant resulted in the out-of-frame skipping of exon 13 and that this variant transcript is not stably expressed based on an allelic imbalance assay on patient-derived RNA (PMID: 19471317, 22505045, 31143303). This variant has been reported in at least three individuals affected with breast and ovarian cancer (PMID: 22711857, 27741520, 28637432) and also in suspected hereditary breast and ovarian cancer families (PMID: 22505045, 22762150). Two similar variants at this nucleotide position, c.4484G>T and c.4484G>C, have been reported in individuals and families affected with breast and ovarian cancer (PMID: 10571952, 21120943, 22762150, 24607278, 27425403) and shown by RNA analysis to cause out-of-frame skipping of exon 13 (PMID: 10571952, 12915465, 21120943, 22505045, 24607278). 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	Jan 30, 2024	The c.4484G>A pathogenic mutation (also known as p.R1495K), located in coding exon 12 of the BRCA1 gene, results from a G to A substitution at nucleotide position 4484. The amino acid change results in arginine to lysine at codon 1495, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 12, which makes it likely to have some effect on normal mRNA splicing. RNA studies demonstrated that this mutation leads to skipping of coding exon 12, which results in a transcript subject to nonsense-mediated mRNA decay (Ambry internal data; Houdayer C et al. Hum Mutat. 2012 Aug;33(8):1228-38). Another alteration impacting the same donor/acceptor site (c.4484G>T) has been shown to have a similar impact on splicing (Ambry internal data; Yang Y et al. Hum. Mol. Genet. 2003 Sep;12:2121-31; Caux-Moncoutier V et al. Hum. Mutat. 2011 Mar;32:325-34; Houdayer C et al. Hum. Mutat. 2012 Aug;33:1228-38). This nucleotide position is highly conserved in available vertebrate species. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -

Hereditary breast ovarian cancer syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 28, 2023	This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 1495 of the BRCA1 protein (p.Arg1495Lys). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 22711857, 22762150, 23633455, 27741520, 29446198). ClinVar contains an entry for this variant (Variation ID: 37597). 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 tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in skipping of exon 13 (also called exon 14 in published literature) and introduces a premature termination codon (PMID: 19471317, 22505045; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. This variant disrupts the c.4484G nucleotide in the BRCA1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (Invitae). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 27, 2022	Variant summary: BRCA1 c.4484G>A (p.Arg1495Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: One predicts the variant abolishes a canonical 5' splicing donor site and two predict the variant weakens the 5' donor site. At least two publications have provided experimental evidence to demonstrate that this variant does indeed affect mRNA splicing, indicating that it results in the skipping of exon 13 which produces a frameshift, ultimately leading to a premature stop codon (e.g. Houdayer_2012, Wangensteen_2019). The variant was absent in 251172 control chromosomes (gnomAD). c.4484G>A has been reported in the literature in multiple individuals affected with breast/ovarian cancer, including those with a family history of breast/ovarian cancer (e.g. Lecarpentier_2012, Alsop_2012, Fernandes_2016, Turner_2019, Ren_2021, Solano_2021). These data strongly suggest that the variant is associated with disease. Eight submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as pathogenic (n=6) or likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic. -

Familial cancer of breast Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Center for Precision Medicine, Meizhou People's Hospital

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Malignant tumor of breast Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	.;T;.;.;.;.;.;T;.
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.88	D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.74	D
MetaRNN	Uncertain	0.49	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.45	D
MutationAssessor	Benign	1.9	.;L;.;.;.;.;.;.;.
MutationTaster	Benign	0.94	D;D;D;D;D;D;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.95	N;N;.;N;N;N;N;N;N
REVEL	Pathogenic	0.65
Sift	Uncertain	0.020	D;D;.;T;D;T;D;D;D
Sift4G	Benign	0.52	T;T;T;T;T;T;.;.;T
Polyphen		0.17, 0.84	.;B;.;.;.;.;.;P;.
Vest4		0.52
MVP		0.86
MPC		0.091
ClinPred		0.78	D
GERP RS		5.0
Varity_R		0.16
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.51		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.51		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs80357389; hg19: chr17-41228505;