rs80357389

chr17-43076488-C-Achr17-43076488-C-Gchr17-43076488-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PM5 PP3 PP5_Very_Strong

The NM_007294.4(BRCA1):c.4484G>T(p.Arg1495Met) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000274 in 1,461,350 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1495T) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense, splice_region
• Scores: Splicing: ADA: 0.9994
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:24
• 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 13 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-G is described in ClinVar as [Pathogenic]. Clinvar id is 245697.Status of the report is reviewed_by_expert_panel, 3 stars.
• 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-A is Pathogenic according to our data. Variant chr17-43076488-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 37598.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-43076488-C-A is described in Lovd as [Pathogenic]. Variant chr17-43076488-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.4484G>T	p.Arg1495Met	missense_variant, splice_region_variant	13/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.4484G>T	p.Arg1495Met	missense_variant, splice_region_variant	13/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251172 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135788

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461350 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726982

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:24

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:9

Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
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, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	May 01, 2012	- -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Aug 26, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Pathway Genomics	Oct 30, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 26, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	This missense variant replaces arginine with methionine at codon 1495 and causes a G>T nucleotide substitution at the last nucleotide of exon 13 of the BRCA1 gene. Multiple RNA studies on carrier RNA and minigene splicing assay have consistently found that this variant causes the out-of-frame skipping of exon 13 resulting in a premature termination codon (PMID: 10571952, 12915465, 21120943, 22505045, 23451180, 24607278, 31843900). This variant has been reported in multiple individuals and families affected with breast and ovarian cancer (PMID: 10571952, 18092194, 18159056, 18694767, 21120943, 21324516, 22476429, 23096355, 23374397, 24607278, 27914478, 28423363, 31843900). This variant has been reported with family history and co-segregation likelihood ratios for pathogenicity of 5.28 and 2.42, respectively (PMID: 17924331, 24607278). This variant has been identified in 1/251172 chromosomes 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	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Jul 17, 2021	ACMG classification criteria: PS3 strong, PS3, PS4 strong, PS4, PM2 moderate, PM2, PP1 moderate, PP3 supporting -

Hereditary breast ovarian cancer syndrome Pathogenic:5

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	Invitae	Jan 11, 2024	This sequence change replaces arginine, which is basic and polar, with methionine, which is neutral and non-polar, at codon 1495 of the BRCA1 protein (p.Arg1495Met). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs80357389, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast and ovarian cancer (PMID: 10571952, 10923033, 22144684, 23096355, 24607278). It has also been observed to segregate with disease in related individuals. This variant is also known as 4603G>T and c.4547G>T. ClinVar contains an entry for this variant (Variation ID: 37598). 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 and introduces a premature termination codon (PMID: 10571952, 12915465, 21120943, 24607278; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. 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	Jul 31, 2016	Variant summary: The BRCA1 c.4484G>T (p.Arg1495Met) variant causes a missense change involving a conserved nucleotide, located at the most 3' position, i.e., the last nucleotide of exon 13. It is predicted to disrupt the natural splice donor site and cause abnormal splicing. 5/5 splicing prediction tools, predict alterations to splicing, consistent with the observed functional studies that implicate an affect on splicing. The variant of interest was observed in a large, broad control population, ExAC, with an allele frequency of 1/121358, which does not exceed the estimated maximal expected allele frequency for a pathogenic BRCA1 variant of 1/1000. The variant of interest has been reported in multiple affected individuals via publications, along with multiple reputable databases/clinical laboratories citing the variant as "pathogenic." Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 15, 2023	The p.Arg1495Met variant in BRCA1 has been reported in more than 30 individuals with hereditary breast and ovarian cancer (HBOC) and segregated with disease in at least 4 affected relatives from 2 families (Santos 2014 PMID: 24607278, Ripamonti 2013 PMID: 23374397, Breast Cancer Information Core (BIC) database). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 37598) and has been identified in 0.0009% (1/113592) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with the frequency of HBOC in the general population. This variant is located in the last three bases of the exon, which is part of the 5’ splice region and several in vitro functional studies using patient RNA and minigene splicing assays have shown that the p.Arg1495Met causes skipping of exon 13 (Colombo 2013 PMID: 23451180, Santos 2014 PMID: 24607278, Houdayer 2012 PMID: 22505045), leading to resulting in a frameshift and resulting in a premature termination codon. In addition, additional variants involving this codon (p.Arg1495Thr and p.Arg1495Lys) have been identified in several individuals with HBOC and are classified as pathogenic in ClinVar by the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) and several clinical laboratories, respectively. In summary, the p.Arg1495Met variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PS4, PM2_Supporting, PM5, PP1, PS3_Moderate. -
Pathogenic, criteria provided, single submitter	research	Genetics Program, Instituto Nacional de Cancer	Nov 01, 2021	- -

not provided Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The BRCA1 p.Arg1495Met variant was identified in 7 of 8214 proband chromosomes (frequency: 0.0009) from individuals or families with breast and/or ovarian cancer or fallopian tube cancer (Zhang 2011, Shattuck-Eidens 1997, Nedelcu 2002, Aziz 2001, John 2007, Pilato 2010). The variant was also identified in the following databases: dbSNP (ID: rs80357389) as “With Pathogenic allele”, ClinVar and Clinvitae (12x - classified as pathogenic by Ambry Genetics, GeneDx, Pathway Genomics, Quest Diagnostics, GeneKor, Univ. of Cambridge, Color Genomics, Baylor Miraca Genetics, Invitae, BIC, SCRP, COGR), COGR (2x - classified as pathogenic by Sinai Health System and COGR consensus), LOVD 3.0 (3x classified as affects function), UMD-LSDB (12x classified as causal), BIC Database (27 submissions, classification pending), and the ARUP Laboratories (classified as definitely pathogenic). The variant was not identified in COSMIC, MutDB, or Zhejiang Colon Cancer databases. The variant was also identified by our laboratory in 1 individual with breast cancer. The variant was identified in control databases in 1 of 245958 chromosomes at a frequency of 0.000004 (one individual of European non-Finnish ethnicity; freq. 0.000009) (Genome Aggregation Consortium Feb 27, 2017). This variant was observed by RT-PCR to result increased levels of alternative transcripts demonstrating both an out-of-frame deletion of exon 14 as well as an in-frame deletion of exons 14 and 15 (Santos 2014). Together with co-segregation data the authors conclude that this variant is considered pathogenic. A humanized mouse model system demonstrated that this variant causes aberrant splicing resulting in the deletion of exon 14 due to possible disruption of cis-acting splicing regulatory elements (Yang 2003). The p.Arg1495Met residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The p.Arg1495Met variant occurs in the last base of the exon. This position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. In addition, 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 04, 2022	Published splicing studies demonstrate a damaging effect: Exonic splice resulting in out-of-frame skipping of exon 13, as well as minor amounts of transcript with in-frame skipping of exons 13-14 (also referred to as exons 14 and 15 in the literature) (Ozcelik 1999, Yang 2003, Houdayer 2012, Colombo 2013, Santos 2014); Observed in multiple individuals with personal and/or family histories of breast and ovarian cancer, segregating with cancer in at least one of these families (Aziz 2001, Caux-Moncoutier 2011, Zhang 2011, Lara 2012, Ripamonti 2013, Santos 2014, Pal 2015, Finch 2015, Pellegrino 2016, Brianese 2017); Multifactorial studies suggest this variant is associated with breast and ovarian cancer (Lindor 2012); Not observed at significant frequency in large population cohorts (gnomAD); Also known as 4603G>T; This variant is associated with the following publications: (PMID: 25782689, 21324516, 27163896, 12915465, 26219728, 10571952, 21447777, 26913838, 23374397, 24607278, 26287763, 21120943, 25896959, 24916970, 18092194, 23096355, 17924331, 27914478, 27225819, 29116469, 28465148, 28475402, 28781887, 30283497, 29907814, 28423363, 31013702, 30606148, 30765603, 30159786, 22505045, 32885271, 29446198, 11263928, 33087888, 23451180, 32427313, 30787465, 21990134, 15343273, 22737296) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 09, 2019	In the published literature, it has been reported in women affected with breast cancer (PMIDs: 18694767 (2008), 26287763 (2015)), ovarian cancer (PMIDs: 10571952 (1999), 27914478 (2016)), and fallopian tube cancer (PMID: 11263928 (2001)). Functional studies have shown that this variant causes skipping of BRCA1 exon 14 (PMIDs: 12915465 (2003), 22505045 (2012), 12915465 (2003)). Based on the available information, this variant is classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Nov 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 27, 2021	The c.4484G>T pathogenic mutation (also known as p.R1495M), located in coding exon 12 of the BRCA1 gene, results from a G to T substitution at nucleotide position 4484. The amino acid change results in arginine to methionine at codon 1495, an amino acid with 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. The c.4484G>T mutation has been reported in hereditary breast and ovarian cancer patients and multiple, independent splicing studies have demonstrated that it leads to exon skipping and predicted premature protein truncation (Ambry internal data; Ozcelik H et al. Hum Mutat, 1999;14:540-1; Aziz S et al. Gynecol. Oncol. 2001 Mar;80:341-5; Yang Y et al. Hum. Mol. Genet. 2003 Sep;12:2121-31; Tommasi S et al. Mutat. Res. 2008 Sep;644:64-70; Caux-Moncoutier V et al. Hum. Mutat. 2011 Mar;32:325-34; Lu W et al. Fam Cancer, 2012 Sep;11:381-5; Houdayer C et al. Hum. Mutat. 2012 Aug;33:1228-38; Lara K et al. Biol. Res. 2012;45:117-30; Ripamonti CB et al. BMC Cancer, 2013 Feb;13:46; Dodova RI et al. BMC Cancer, 2015 Jul;15:523; Maistro S et al. BMC Cancer. 2016 Dec;16:934; Palmero EI et al. Sci Rep, 2018 06;8:9188; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620; Marchetti C et al. Ann Surg Oncol, 2018 Nov;25:3701-3708; de Souza Timoteo AR et al. Breast Cancer Res Treat, 2018 Dec;172:637-646; Cotrim DP et al. BMC Cancer, 2019 Jan;19:4; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879; Artioli G et al. Gynecol Oncol, 2021 Jun;161:755-761). This mutation was also reported in a patient with endometrial cancer who also had family history of ovarian cancer (Vietri MT et al. Med Oncol, 2021 Jan;38:13). In addition, this alteration has been classified as pathogenic (p>0.99) by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, and mutation co-occurrence (Easton DF et al. Am. J. Hum. Genet. 2007 Nov;81:873-83; Lindor NM et al. Hum. Mutat. 2012 Jan;33:8-21; Vallee MP et al. Hum. Mutat. 2012 Jan;33:22-8). Of note, this alteration is also designated as 4603G>T in published literature. This nucleotide position is highly conserved in available vertebrate species. In addition, In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as a pathogenic mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 30, 2023	This missense variant replaces arginine with methionine at codon 1495 and causes a G>T nucleotide substitution at the last nucleotide of exon 13 of the BRCA1 gene. Multiple RNA studies on carrier RNA and minigene splicing assay have consistently found that this variant causes the out-of-frame skipping of exon 13 resulting in a premature termination codon (PMID: 10571952, 12915465, 21120943, 22505045, 23451180, 24607278, 31843900). This variant has been reported in multiple individuals and families affected with breast and ovarian cancer (PMID: 10571952, 18092194, 18159056, 18694767, 21120943, 21324516, 22476429, 23096355, 23374397, 24607278, 27914478, 28423363, 31843900). This variant has been reported with family history and co-segregation likelihood ratios for pathogenicity of 5.28 and 2.42, respectively (PMID: 17924331, 24607278). This variant has been identified in 1/251172 chromosomes 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. -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneKor MSA

Jul 01, 2016

- -

Breast and/or ovarian cancer Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Jun 28, 2022

- -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 23, 2017

- -

Hereditary breast ovarian cancer syndrome;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1

Pathogenic, no assertion criteria provided

research

King Laboratory, University of Washington

Sep 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	28
DANN	Benign	0.96
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.86	D;T;D;D;T;D;T;T;T
M_CAP	Pathogenic	0.83	D
MetaRNN	Uncertain	0.58	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.51	D
MutationTaster	Benign	0.93	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-2.8	D;N;.;N;N;N;D;N;D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0020	D;D;.;D;D;D;D;D;D
Sift4G	Uncertain	0.014	D;D;D;D;D;D;.;.;D
Polyphen		0.47, 0.99	.;P;.;.;.;.;.;D;.
Vest4		0.81
MVP		0.89
MPC		0.16
ClinPred		0.85	D
GERP RS		5.0
Varity_R		0.11
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.60		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.60		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;