17-43047676-G-C

Variant names:

• chr17-43047676-G-C
• rs1800751
• NM_007294.4:c.5434C>G

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PM2 PP3 PP5_Very_Strong

The NM_007294.4(BRCA1):​c.5434C>G​(p.Pro1812Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. P1812T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12 U:3
• Conservation: PhyloP100: 3.68
• Publications: 44 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 13 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 16 benign, 82 uncertain in NM_007294.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.831
• PP5: Variant 17-43047676-G-C is Pathogenic according to our data. Variant chr17-43047676-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 37670.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.5434C>G	p.Pro1812Ala	missense_variant	Exon 22 of 23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.5434C>G	p.Pro1812Ala	missense_variant	Exon 22 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251488 AF XY: 0.00000736

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461886 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12 Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:5 Uncertain:2

May 01, 2016

Department of Medical Genetics, University Hospital of North Norway

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

May 01, 2012

Sharing Clinical Reports Project (SCRP)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jul 01, 2015

Department of Medical Genetics, Oslo University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 01, 2017

Genologica Medica

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 11, 2020

Genetics and Molecular Pathology, SA Pathology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 05, 2009

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Uncertain significance

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

not provided Pathogenic:3

Jul 13, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 16, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA1 c.5434C>G; p.Pro1812Ala variant (rs1800751), also known as 5553C>G, is reported in the literature in several individuals with a personal and family history of hereditary breast and ovarian cancer and the variant is reported to segregate with disease in two families (Diez 2003, Gaildrat 2010, Jarhelle 2016, Konstantopoulou 2008, Laitman 2011, Martinez-Ferrandis 2003, Stavropoulou 2013). RNA studies in patient cells and in vitro splicing assays have shown that this variant causes skipping of this exon leading to a truncated protein product and disrupting a functional domain (Gaildrat 2010, Jarhelle 2016). This variant is also described as pathogenic or likely pathogenic by several sources in the ClinVar database (Variation ID: 37670). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. Based on available information, this variant is classified as pathogenic References: Diez O et al. Analysis of BRCA1 and BRCA2 genes in Spanish breast/ovarian cancer patients: a high proportion of mutations unique to Spain and evidence of founder effects. Hum Mutat. 2003 Oct;22(4):301-12. PMID: 12955716. Gaildrat P et al. The BRCA1 c.5434C>G (p.Pro1812Ala) variant induces a deleterious exon 23 skipping by affecting exonic splicing regulatory elements. J Med Genet. 2010 Jun;47(6):398-403. PMID: 20522429. Jarhelle E et al. Characterization of BRCA1 and BRCA2 variants found in a Norwegian breast or ovarian cancer cohort. Fam Cancer. 2017 Jan;16(1):1-16. PMID: 27495310. Kaufman B et al. The P1812A and P25T BRCA1 and the 5164del4 BRCA2 mutations: occurrence in high-risk non-Ashkenazi Jews. Genet Test. 2006 Fall;10(3):200-7. PMID: 17020472. Konstantopoulou I et al. Greek BRCA1 and BRCA2 mutation spectrum: two BRCA1 mutations account for half the carriers found among high-risk breast/ovarian cancer patients. Breast Cancer Res Treat. 2008 Feb;107(3):431-41. PMID: 17453335. Laitman Y et al. Germline mutations in BRCA1 and BRCA2 genes in ethnically diverse high risk families in Israel. Breast Cancer Res Treat. 2011 Jun;127(2):489-95. PMID: 20960228. Martinez-Ferrandis JI et al. Mutational analysis of BRCA1 and BRCA2 in Mediterranean Spanish women with early-onset breast cancer: identification of three novel pathogenic mutations. Hum Mutat. 2003 Nov;22(5):417-8. PMID: 14517958. Singh J et al. Screening of over 1000 Indian patients with breast and/or ovarian cancer with a multi-gene panel: prevalence of BRCA1/2 and non-BRCA mutations. Breast Cancer Res Treat. 2018 Jul;170(1):189-196. PMID: 29470806.

Aug 02, 2017

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is denoted BRCA1 c.5434C>G at the cDNA level, p.Pro1812Ala (P1812A) at the protein level, and results in the change of a Proline to an Alanine (CCA>GCA). Using alternate nomenclature, this variant would be defined as BRCA1 5553C>G. This variant has been observed in several individuals with a personal and family history consistent with Hereditary Breast and Ovarian Cancer syndrome, segregating with disease in two kindreds (Martinez-Ferrandis 2003, Diez 2003, Kaufman 2006, Gaildrat 2010, Laitman 2011, Stavropoulou 2013, Jarhelle 2016). RNA and minigene assays have demonstrated that this variant causes skipping of exon 22, published as exon 23, in most transcripts, leading to a truncated protein product and disrupting the second BRCT domain (Gaildrat 2010, Jarhelle 2016). When present in a full-length transcript, BRCA1 Pro1812Ala has been found to cause a slight reduction in transcriptional activity, protein binding capacity, and thermostability (Kaufman 2006, Drikos 2009). Although the nucleotide substitution results in the change of a Proline to an Alanine at codon 1812, and may also be called Pro1812Ala in the literature, we are using the nucleotide nomenclature to refer to the variant since the defect is determined to be one of splicing rather than a resulting missense variant. BRCA1 c.5434C>G was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. The nucleotide which is altered, a cytosine (C) at base 5434, is conserved through mammals. Based on current evidence, we consider BRCA1 c.5434C>G to be a likely pathogenic variant.

Hereditary cancer-predisposing syndrome Pathogenic:2

Dec 05, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces proline with alanine at codon 1812 of the BRCA1 protein. Computational prediction tool is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). This variant also causes a C>G nucleotide substitution at nucleotide 5434 in exon 22 of the BRCA1 gene. RNA studies have reported that this variant caused the out-of-frame skipping of exon 22 that disrupted the BRCT domain in the encoded protein (PMID: 20522429, 21673748, 27495310). It has been reported that there is no wild type transcript produced from the mutant allele (ClinVar SCV000665890.4). Cells transfected with the mutant allele show defective BRCA1 function in a haploid cell proliferation assay (PMID: 30209399). This variant has been observed in many individuals affected with breast and ovarian cancer (PMID: 12955716, 14517958, 17020472, 17453335, 19452558, 20522429, 23536787, 27495310, 29470806) and has been shown to segregate with disease in five unrelated families (PMID: 34597585). This variant has also been identified in 1/251488 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.

Jul 15, 2020

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5434C>G variant (also known as p.P1812A), located in coding exon 21 of the BRCA1 gene, results from a C to G substitution at nucleotide position 5434. The proline at codon 1812 is replaced by alanine, an amino acid with highly similar properties. This alteration has been detected in many breast and ovarian cancer cohorts (Mart&iacute;nez-Ferrandis JI et al. Hum. Mutat. 2003 Nov;22:417-8; D&iacute;ez O et al. Hum. Mutat. 2003 Oct;22:301-12; Kaufman B et al. Genet. Test. 2006;10:200-7; Stavropoulou AV et al. PLoS ONE, 2013 Mar;8:e58182; Jarhelle E et al. Fam. Cancer. 2017 01;16:1-16; Heramb C et al. Hered Cancer Clin Pract. 2018 Jan;16:3). Numerous studies have reported that this alteration causes skipping of coding exon 21 (also called exon 23 in the literature) and although one study shows semi-quantitative data indicating the splice defect may be leaky, another unpublished study shows that there is no wildtype transcript produced from the altered allele (Ambry internal data; Gaildrat P et al. J. Med. Genet. 2010 Jun;47:398-403; Houdayer C et al. Hum. Mutat. 2012 Aug;33:1228-38; Jarhelle E et al. Fam. Cancer. 2017 01;16:1-16; personal communication). Using the BDGP and ESEfinder splice site prediction tools, this alteration is to predicted to strengthen a cryptic splice acceptor site that becomes stronger than the native splice acceptor site; however, there is also functional evidence that this variant negatively impacts a splice enhancer site (Gaildrat P et al. J. Med. Genet. 2010 Jun;47:398-403). In a haploid cell survival assay, which can measure both RNA and protein effects, this variant was non-functional with evidence supporting a splice defect (Findlay GM et al. Nature, 2018 10;562:217-222). Several functional studies have been conducted on the missense substitution and have shown modest defects in transcription activation, thermostability and affinity for BRIP1 binding (Kaufman B et al. Genet. Test. 2006;10:200-7; Drikos I et al. Proteins. 2009 Nov;77:464-76). Based on internal structural analysis, this amino acid substitution will result in greater local structural destabilization than other nearby pathogenic alterations (Clapperton JA et al. Nat. Struct. Mol. Biol. 2004 Jun;11:512-8; Ambry internal data). This nucleotide position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Hereditary breast ovarian cancer syndrome Pathogenic:1

Aug 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 1812 of the BRCA1 protein (p.Pro1812Ala). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs1800751, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 14517958, 17020472, 17453335, 20522429, 27495310, 29470806). It has also been observed to segregate with disease in related individuals. This variant is also known as 5553C>G. ClinVar contains an entry for this variant (Variation ID: 37670). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 17020472, 19452558, 30209399). Studies have shown that this missense change results in skipping of exon 22, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 20522429, 22505045, 27495310). For these reasons, this variant has been classified as Pathogenic.

Fanconi anemia, complementation group S Pathogenic:1

Oct 22, 2024

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Uncertain:1

Jan 31, 2014

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

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.098	D
BayesDel_noAF	Uncertain	0.13
CADD	Benign	22
DANN	Uncertain	1.0
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.42	T
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	0.54	D
PhyloP100		3.7
PROVEAN	Benign	-0.43	N
REVEL	Uncertain	0.43
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.59
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.64
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		3.0
SpliceAI score (max)		0.18		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1800751; hg19: chr17-41199693;