rs80358042

Variant names:

• chr17-43106455-C-A
• rs80358042
• NM_007294.4:c.212+1G>T

Your query was ambiguous. Multiple possible variants found:

• chr17-43106455-C-A
• chr17-43106455-C-G
• chr17-43106455-C-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_007294.4(BRCA1):​c.212+1G>T variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.000000702 in 1,423,700 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: BRCA1 NM_007294.4 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:13
• Conservation: PhyloP100: 4.11
• Publications: 40 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):

• breast-ovarian cancer, familial, susceptibility to, 1

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

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, 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 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.013948498 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.8, offset of 12, new splice context is: ttgGTaatg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-43106455-C-A is Pathogenic according to our data. Variant chr17-43106455-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 54465.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.212+1G>T		splice_donor_variant, intron_variant	Intron 4 of 22	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.212+1G>T		splice_donor_variant, intron_variant	Intron 4 of 22	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.02e-7 AC: 1 AN: 1423700 Hom.: 0 Cov.: 27 AF XY: 0.00000141 AC XY: 1 AN XY: 710042

African (AFR) AF: 0.00 AC: 0 AN: 32628

American (AMR) AF: 0.00 AC: 0 AN: 44444

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25862

East Asian (EAS) AF: 0.00 AC: 0 AN: 39376

South Asian (SAS) AF: 0.00 AC: 0 AN: 84258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53272

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5352

European-Non Finnish (NFE) AF: 9.26e-7 AC: 1 AN: 1079418

Other (OTH) AF: 0.00 AC: 0 AN: 59090

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: reviewed by expert panel

Submissions by phenotype

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

Jun 21, 1999

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 18, 2019

Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 0.998791 -

Jan 05, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.212+1G>T variant of the BRCA1 gene is expected to affect mRNA splicing and result in an absent or disrupted protein product. This variant has been reported in multiple individuals with breast, ovarian and/or prostate cancer (PMID: 9333265, 11802209, 22516946, 22970155, 26848529, 28724667, 29752822, 29770616, 30702160). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Truncating variants in BRCA1 are known to be pathogenic (PMID: 21989022, 17661172, 22762150). Therefore, the c.212+1G>T variant of the BRCA1 gene is classified as pathogenic. -

Jun 04, 2012

Sharing Clinical Reports Project (SCRP)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 02, 2015

Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 28, 2017

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

not provided Pathogenic:2

Jan 01, 2020

GeneKor MSA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant occurs in the first base of intron 4 of the BRCA1 gene. This position is conserved in the human and other genomes and might be involved in mRNA processing. Therefore, this variant is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is also known as IVS5+1G>T in the literature. This variant has been reported in the literature in individuals and families with breast and/or ovarian cancer (PMID: 9333265, 11802209) as well as in an individual with prostate cancer (PMID: 22516946). The mutation database ClinVar contains entries for this variant (Variation ID: 54465). -

Apr 06, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is denoted BRCA1 c.212+1G>T or IVS4+1G>T and consists of a G>T nucleotide substitution at the +1 position of intron 4 of the BRCA1 gene. This variant is also known as BRCA1 331+1G>T or IVS5+1G>T using alternate nomenclature. The variant destroys a canonical splice donor site and has been shown to increase the usage of an upstream cryptic splice site and result in a truncated protein (Meindl 2002, Wappenschmidt 2012). This variant has been reported in high-risk breast and/or ovarian cancer families and in at least one prostate cancer case (Shattuck-Eidens 1997, Saxena 2002, Kwong 2012, Leongamornlert 2012). We consider this variant to be pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Sep 26, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.212+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 3 of the BRCA1 gene. This alteration has been identified in many, primarily Chinese, breast and/or ovarian and prostate cancer cohorts (Shattuck-Eidens et al. JAMA. 1997; 278:1243-1250; Choi MC et al. J Gynecol Oncol, 2018 Jul;29:e43; Li JY et al. Int. J. Cancer, 2019 01;144:281-289; Bhaskaran SP et al. Int. J. Cancer, 2019 Aug;145:962-973; Sun J et al. Clin. Cancer Res., 2017 Oct;23:6113-6119; Shi T et al. Int. J. Cancer, 2017 05;140:2051-2059; Leongamornlert D et al. Br. J. Cancer, 2012 May;106:1697-701). RNA experiments have shown that this alteration leads to the use of a cryptic splice donor site 22 nucleotides upstream of the native, leading to an out of frame transcript with a predicted alternate stop codon (Ambry internal data; Meindl et al. Int. J. Cancer. 2002; 97: 472–480). Close match substitutions at this position have shown the same splice defect (Ambry internal data; Houdayer C et al. Hum. Mutat., 2012 Aug;33:1228-38; Friedman LS et al. Am. J. Hum. Genet., 1995 Dec;57:1284-97; Menéndez M et al. Breast Cancer Res. Treat., 2012 Apr;132:979-92Sanz DJ et al. Clin. Cancer Res., 2010 Mar;16:1957-67). This nucleotide position is highly conserved in available vertebrate species. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on the majority of available evidence to-date, this alteration is classified as a disease-causing mutation. -

Oct 25, 2021

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes a G to T nucleotide substitution at the +1 position of intron 4 of the BRCA1 gene. RNA studies of this variant and two different SNV that disrupt c.212+1G found aberrant splicing resulting in the deletion of 22 nucleotides from the 3' end of the exon, which is predicted to cause frameshift and nonsense-mediated decay (PMID: 11802209, 23239986). This variant has intermediate impact on BRCA1 function in a haploid human cell proliferation assay (PMID: 30209399). This variant has been reported in individuals affected with breast and ovarian cancer (PMID: 9333265, 11802209, 12442273, 22970155, 28724667, 2975282, 29770616, 33471991; Eniu et al, 2017 poster, Annals of Oncology v43-v67. 10.1093/annonc/mdx362; Gomez-Flores-Ramos et al, 2020, doi: 10.20944/preprints202008.0718.v1; Color internal data) and an individual with prostate cancer (PMID: 22516946). 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. -

Hereditary breast ovarian cancer syndrome Pathogenic:2

Jan 31, 2014

Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Dec 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 4 of the BRCA1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of BRCA1-related conditions (PMID: 9333265, 11802209, 22516946, 22970155, 26848529). This variant is also known as IVS5+1G>T. ClinVar contains an entry for this variant (Variation ID: 54465). Studies have shown that disruption of this splice site results in activation of a cryptic splice site, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 20215541, 22505045; internal data). For these reasons, this variant has been classified as Pathogenic. -

Malignant tumor of breast Pathogenic:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The c.212+1G>T variant was identified in 2 of 3574 proband chromosomes (frequency: 0.001) from individuals or families with hereditary breast and ovarian cancer (Meindl 2002, Shattuck-Eidens 1997). The variant was also identified in dbSNP (ID: rs80358042) “With pathogenic allele”, Clinvitae database (1X as pathogenic), LOVD, ARUP Laboratories BRCA Mutations Database (as definitely pathogenic), the ClinVar database (classified as a pathogenic variant) and the BIC database (5X with clinical importance). The c.212+1G>T variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	32
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.97	D
PhyloP100		4.1
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.9
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
Splicevardb		3.0
SpliceAI score (max)		0.65		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.65		Position offset: 1

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

Other links and lift over

dbSNP: rs80358042; hg19: chr17-41258472;