17-43106453-T-C

Variant names:

• chr17-43106453-T-C
• rs80358083
• NM_007294.4:c.212+3A>G

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 PVS1 PP4_Strong

This summary comes from the ClinGen Evidence Repository: The c.212+3A>G variant is an intronic variant occurring in intron 4 of the BRCA1 gene. This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met). This variant is reported to result in aberrant mRNA splicing. A combination of RT-PCR from patient samples and mini-gene assays demonstrated that the variant impacts splicing by skipping of 22nt from the 3' end of the exon, reported by five studies (PMIDs: 22505045, 11802209, 20215541, 21673748, 24667779). Two of these studies also reported skipping of exon 4 (PMIDs: 20215541, 24667779). Allele-specific expression was reported by one assay on patient-derived material (PMID:22505045), which showed no WT transcript from the variant allele. This is in agreement with two minigene assays (PMIDs: 21673748, 24667779). One study reported no impact on splicing but no results are shown to assess whether the 22nt skipping event (that is seen in controls at low level) was increased (PMID:16619214), and therefore, has been excluded from consideration when assessing the splicing impact of this variant. Appropriate code strength determined by comparison of results to PVS1 decision tree (PVS1 (RNA) met). Reported by one calibrated study to exhibit protein function similar to pathogenic control variants (PMID:30209399) (PS3 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 1615.48 (based on Co-occurrence LR=1.298; Family History LR=1245.06), above the threshold for Very strong evidence towards pathogenicity (LR >350) (PP4_Very strong met; PMID:17924331, 31853058).In summary, this variant meets the criteria to be classified as a Pathogenic variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PVS1 (RNA), PS3, PP4_Very strong). LINK:https://erepo.genome.network/evrepo/ui/classification/CA001412/MONDO:0011450/092

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: BRCA1 NM_007294.4 splice_region, intron
• Scores: Splicing: ADA: 0.9986
• Clinical Significance: Pathogenic reviewed by expert panel P:16 U:1 O:1
• Conservation: PhyloP100: 1.29
• Publications: 27 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 16 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.212+3A>G		splice_region_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+3A>G		splice_region_variant, intron_variant	Intron 4 of 22	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 7.03e-7 AC: 1 AN: 1422054 Hom.: 0 Cov.: 27 AF XY: 0.00000141 AC XY: 1 AN XY: 709150

African (AFR) AF: 0.00 AC: 0 AN: 32590

American (AMR) AF: 0.00 AC: 0 AN: 44302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25814

East Asian (EAS) AF: 0.00 AC: 0 AN: 39368

South Asian (SAS) AF: 0.00 AC: 0 AN: 83956

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53252

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5328

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1078448

Other (OTH) AF: 0.00 AC: 0 AN: 58996

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152220 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74358

African (AFR) AF: 0.00 AC: 0 AN: 41464

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5208

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68050

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16 Uncertain:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:4 Other:1

Feb 17, 2010

Sharing Clinical Reports Project (SCRP)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Breast Cancer Information Core (BIC) (BRCA1)

Significance: not provided

Review Status: no classification 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

Jan 24, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 08, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes an A to G nucleotide substitution at the +3 position of intron 4 of the BRCA1 gene. Several RNA studies have reported that this variant results in the skipping of exon 4 and/or a partial deletion of exon 4, which are predicted to cause an in-frame deletion in the functionally important RING domain and frameshift, respectively (PMID: 12037674, 21673748, 22505045, 29021971). A functional study has reported that this variant impacts BRCA1 function in a haploid cell proliferation assay (PMID: 30209399). This variant has been reported in multiple individuals and families affected with breast and/or ovarian cancer (PMID: 9150151, 10090482, 15026808, 23199084, 28294317, 29487695). This variant also has been reported as a Belgian founder mutation that was also observed in other populations (PMID: 10595255, 23199084, 29021971). This variant has been identified in 1/31400 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.

Hereditary breast ovarian cancer syndrome Pathogenic:4

Jul 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 4 of the BRCA1 gene. It does not directly change the encoded amino acid sequence of the BRCA1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs80358083, gnomAD 0.007%). This variant has been observed in individual(s) with breast and ovarian cancer (PMID: 9150151, 10090482, 10595255, 15026808, 16619214, 28294317). It has also been observed to segregate with disease in related individuals. This variant is also known as IVS5+3A>G. ClinVar contains an entry for this variant (Variation ID: 54467). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 21990134). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 21673748, 24667779). For these reasons, this variant has been classified as Pathogenic.

Jul 21, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRCA1 c.212+3A>G alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Computational tools predict a significant impact on normal splicing: Two predict the variant weakens a canonical 5' donor site and one predicts the variant abolishes this site. One predicts the variant has no significant impact on splicing. At least one publication reports experimental evidence that this variant affects mRNA splicing (Steffensen_2014). The variant was absent in 249100 control chromosomes (gnomAD). c.212+3A>G has been observed in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g., Peelen_1997, van Heetvelde_2018). These data indicate that the variant is very likely to be associated with disease. At least one functional study reports experimental evidence evaluating an impact on protein function and showed a damaging effect of this variant on homology directed repair (HDR) activity (e.g. Findlay_2018). HDR assays qualify as a recognized gold standard on the basis of updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) working group. The following publications have been ascertained in the context of this evaluation (PMID: 30209399, 9150151, 29021971, 24667779). ClinVar contains an entry for this variant (Variation ID: 54467). Based on the evidence outlined above, the variant was classified as pathogenic.

Apr 02, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.212+3A>G variant in BRCA1 has been reported in >15 families with hereditary breast and ovarian cancer and is a founder variant in the Belgian population (Claes 1999, Claes 2004, Bhaskaran 2019, Li 2018, Li 2019, Peelen 1997, Breast Information Core Database). This variant was classified as Pathogenic on August 10, 2015 by the ClinGen-approved ENIGMA expert panel (Variation ID 54467). It has also been identified in 0.006% (1/5430) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). In vitro mini-gene assay and RT-PCR on RNA from blood samples or lymphoblastoid cell lines showed increased in-frame skipping of exon 5 and out-of-frame skipping of the last 22 nucleotides of exon 5. Loss of function of the BRCA1 gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian breast cancer. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast and ovarian cancer. ACMG/AMP Criteria applied: PS4, PM2, PS3_Moderate, PVS1_Moderate.

Dec 17, 2015

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

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

not provided Pathogenic:2

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Pathogenic:2

Apr 28, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.212+3A>G intronic pathogenic mutation (also known as IVS5+3A>G) results from an A to G substitution 3 nucleotides after coding exon 3 in the BRCA1 gene. This alteration has been detected in multiple breast and/or ovarian cancer families and is a known Belgian founder mutation, though it has also been reported in German, Dutch, and French families to date (Peelen T. Am. J. Hum. Genet. 1997 May; 60(5):1041-9; Claes K. Br. J. Cancer 2004 Mar; 90(6):1244-51; Claes K. Dis. Markers 1999 Oct; 15(1-3):69-73; Janaviius R. EPMA J 2010 Sep; 1(3):397-412). Although one study utilizing RT-PCR on patient RNA found no effect on normal splicing (Chen X. Hum. Mutat. 2006 May; 27(5):427-35), many other RNA assays show that this alteration results in the use of a cryptic donor site 22 nucleotides upstream from the native site, leading to a frameshift and premature stop codon (Ambry internal data; Meindl A et al. Int J Cancer, 2002 Feb;97:472-80; Houdayer C. Hum. Mutat. 2012 Aug; 33(8):1228-38; Théry JC. Eur. J. Hum. Genet. 2011 Oct; 19(10):1052-8; Steffensen AY. Eur. J. Hum. Genet. 2014 Dec; 22(12):1362-8; Sanz DJ. Clin. Cancer Res. 2010 Mar; 16(6):1957-67). One functional study found that this nucleotide substitution is non-functional in a high-throughput, genome editing, haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). Many other alterations impacting the same donor (c.211A>G, c.212G>A, c.212+1G>T, c.212+1G>A, c.212+2T>C) have been shown to have a similar and complete impact on splicing (Vega A et al. Hum Mutat, 2001 Jun;17:520-1; Caleca L et al. PLoS One, 2014 Feb;9:e86924; Colombo M et al. PLoS One, 2013 Feb;8:e57173; Friedman LS et al. Am J Hum Genet, 1995 Dec;57:1284-97; Meindl A et al. Int J Cancer, 2002 Feb;97:472-80; Houdayer C. Hum. Mutat. 2012 Aug; 33(8):1228-38; Sanz DJ. Clin. Cancer Res. 2010 Mar; 16(6):1957-67). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Sep 02, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes an A to G nucleotide substitution at the +3 position of intron 4 of the BRCA1 gene. Several RNA studies have reported that this variant results in the skipping of exon 4 and/or a partial deletion of exon 4, which are predicted to cause an in-frame deletion in the functionally important RING domain and frameshift, respectively (PMID: 12037674, 21673748, 22505045, 29021971). A functional study has reported that this variant impacts BRCA1 function in a haploid cell proliferation assay (PMID: 30209399). This variant has been reported in multiple individuals and families affected with breast and/or ovarian cancer (PMID: 9150151, 10090482, 15026808, 23199084, 28294317, 29487695). This variant also has been reported as a Belgian founder mutation that was also observed in other populations (PMID: 10595255, 23199084, 29021971). This variant has been identified in 1/31400 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

Nov 04, 2016

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BRCA1-related cancer predisposition Pathogenic:1

Jun 11, 2024

ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.212+3A>G variant is an intronic variant occurring in intron 4 of the BRCA1 gene. This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met). This variant is reported to result in aberrant mRNA splicing. A combination of RT-PCR from patient samples and mini-gene assays demonstrated that the variant impacts splicing by skipping of 22nt from the 3' end of the exon, reported by five studies (PMIDs: 22505045, 11802209, 20215541, 21673748, 24667779). Two of these studies also reported skipping of exon 4 (PMIDs: 20215541, 24667779). Allele-specific expression was reported by one assay on patient-derived material (PMID: 22505045), which showed no WT transcript from the variant allele. This is in agreement with two minigene assays (PMIDs: 21673748, 24667779). One study reported no impact on splicing but no results are shown to assess whether the 22nt skipping event (that is seen in controls at low level) was increased (PMID: 16619214), and therefore, has been excluded from consideration when assessing the splicing impact of this variant. Appropriate code strength determined by comparison of results to PVS1 decision tree (PVS1 (RNA) met). Reported by one calibrated study to exhibit protein function similar to pathogenic control variants (PMID: 30209399) (PS3 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 1615.48 (based on Co-occurrence LR=1.298; Family History LR=1245.06), above the threshold for Very strong evidence towards pathogenicity (LR >350) (PP4_Very strong met; PMID: 17924331, 31853058). In summary, this variant meets the criteria to be classified as a Pathogenic variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PVS1 (RNA), PS3, PP4_Very strong).

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 BRCA1 c.212+3A>G variant was identified in 2 of 1942 proband chromosomes (frequency: 0.001) from individuals or families with breast or ovarian cancer (Chen 2006, Kwong 2018). The variant was also identified in dbSNP (ID: rs80358083) as ""With Pathogenic allele"", ClinVar (classified as pathogenic by five submitters; as likely pathogenic by one submitter and uncertain significance by one submitter) and in LOVD 3.0 (99X as pathogenic). The variant was identified in control databases in 1 of 30976 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 1 of 15010 chromosomes (freq:0.00007), while the variant was not observed in the Other, Latino, European, Ashkenazi Jewish, Finnish, South Asian, African or East Asian populations. The c.212+3A>G variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. Multiple splicing assay studies using RT-PCR analysis on RNA identify the variant causing in-frame skipping of exon 5 and out-of-frame skipping of the last 22 nucleotides of exon 5 (Houdayer 2012, Steffensen 2014, Thery 2011). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.

Familial cancer of breast Pathogenic:1

Center for Precision Medicine, Meizhou People's Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Breast and/or ovarian cancer Uncertain:1

Apr 09, 2015

Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	14
DANN	Benign	0.92
PhyloP100		1.3
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	0.90
Splicevardb		3.0
SpliceAI score (max)		0.63		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.63		Position offset: 3

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

Other links and lift over

dbSNP: rs80358083; hg19: chr17-41258470;