rs80357389

Variant names:

• chr17-43076488-C-A
• rs80357389
• NM_007294.4:c.4484G>T

Your query was ambiguous. Multiple possible variants found:

• chr17-43076488-C-A
• chr17-43076488-C-G
• chr17-43076488-C-T

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PS3 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 (★★). ClinVar reports functional evidence for this variant: "SCV004817666: 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)." and additional evidence is available in ClinVar. 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:29
• Conservation: PhyloP100: 3.88
• Publications: 88 publications found

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 Gene-Disease associations (from GenCC):

• BRCA1-related cancer predisposition

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• breast-ovarian cancer, familial, susceptibility to, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Fanconi anemia, complementation group S

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• pancreatic cancer, susceptibility to, 4

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary breast ovarian cancer syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004817666: 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).; SCV006110167: Studies have shown that this missense change results in skipping of exon 13, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 10571952, 12915465, 21120943, 24607278).; SCV000076589: Studies have shown that this missense change results in skipping of exon 13, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 10571952, 12915465, 21120943, 24607278; internal data).; SCV000605750: 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); SCV000186941: 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).; SCV000537652: 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).; SCV000210177: 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); 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; SCV000296380: published RNA studies have shown this variant causes deleterious exon skipping (PMIDs: 24607278 (2014), 22505045 (2012), 12915465 (2003)).; SCV000591519: 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).
• 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 VariationId is 245697.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: Splicing predictors support a deleterious 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 VariationId is 37598.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007294.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	NM_007294.4	MANE Select	c.4484G>T	p.Arg1495Met	missense splice_region	Exon 13 of 23	NP_009225.1	P38398-1
	BRCA1	NM_001407581.1		c.4550G>T	p.Arg1517Met	missense splice_region	Exon 14 of 24	NP_001394510.1	A0A2R8Y7V5
	BRCA1	NM_001407582.1		c.4550G>T	p.Arg1517Met	missense splice_region	Exon 14 of 24	NP_001394511.1	A0A2R8Y7V5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	ENST00000357654.9	TSL:1 MANE Select	c.4484G>T	p.Arg1495Met	missense splice_region	Exon 13 of 23	ENSP00000350283.3	P38398-1
	BRCA1	ENST00000471181.7	TSL:1	c.4547G>T	p.Arg1516Met	missense splice_region	Exon 14 of 24	ENSP00000418960.2	P38398-7
	BRCA1	ENST00000470026.6	TSL:1	c.4484G>T	p.Arg1495Met	missense splice_region	Exon 13 of 23	ENSP00000419274.2	P38398-1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251172 AF XY: 0.00

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39644

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53222

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111784

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
12	-	-	Breast-ovarian cancer, familial, susceptibility to, 1 (12)
5	-	-	Hereditary breast ovarian cancer syndrome (5)
4	-	-	Hereditary cancer-predisposing syndrome (4)
3	-	-	not provided (3)
1	-	-	Breast and/or ovarian cancer (1)
1	-	-	Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S (1)
1	-	-	Familial cancer of breast (1)
1	-	-	Hereditary breast ovarian cancer syndrome;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1 (1)
1	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.16	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.83	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Uncertain	0.51	D
MutationAssessor	Benign	1.9	L
PhyloP100		3.9
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.014	D
Polyphen		0.47	P
Vest4		0.81
MVP		0.89
MPC		0.16
ClinPred		0.85	D
GERP RS		5.0
Varity_R		0.11
gMVP		0.29
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
Splicevardb		3.0
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

Other links and lift over

dbSNP: rs80357389; hg19: chr17-41228505;