17-43049170-A-G

Variant names:

• chr17-43049170-A-G
• rs398122697
• NM_007294.4:c.5357T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_007294.4(BRCA1):​c.5357T>C​(p.Leu1786Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1786R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:11 U:4
• Conservation: PhyloP100: 5.13
• Publications: 19 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 17 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 15 benign, 78 uncertain in NM_007294.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.918
• PP5: Variant 17-43049170-A-G is Pathogenic according to our data. Variant chr17-43049170-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 91649.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.5357T>C	p.Leu1786Pro	missense_variant	Exon 21 of 23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.5357T>C	p.Leu1786Pro	missense_variant	Exon 21 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251444 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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:11 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary breast ovarian cancer syndrome Pathogenic:3 Uncertain:1

Jun 01, 2019

Cancer Variant Interpretation Group UK, Institute of Cancer Research, London

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Data included in classification: Observed once in 125,722 gnomAD controls. (PM2_sup). Non-functional in SGE haploid BRCA1-assay (Findlay et al. 2018); Lu et al. (2015) homology-directed repair assay PMID: 26689913 (PS3_strong). Variant in BRCT domain (PM1_sup). Data not included in classification: Not observed in 25,773 UK familial cases. UK family 1: Proband was tested in Australia. Molecular report suggests strong segregation with the disease, involving 12 individuals from 5 independent families. Literature: Meyer et al 2003 - PMID: 12938098 (1 family no information about number of individuals). Predicted deleterious by SIFT and MAPP. Predicted benign by Polyphen HumVar and Align GVGD. Additional reports of variant in ClinVar (6), BIC (2) and BRCA1 LOVD (2), UMD(0), HGMD (0). Classified as VUS by Ambry 2017, Gene Dx 2016, Invitae 2018.

May 01, 2020

Breast Center, Key Laboratory of Carcinogenesis and Translational Research

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1786 of the BRCA1 protein (p.Leu1786Pro). This variant is present in population databases (rs398122697, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 12938098, 26689913, 29113215, 32803532; internal data). This variant is also known as 5476C>T. ClinVar contains an entry for this variant (Variation ID: 91649). Invitae Evidence Modeling incorporating data from in vitro 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: 26689913, 29113215, 30209399, 30765603). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Jul 12, 2021

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRCA1 c.5357T>C (p.Leu1786Pro) results in a non-conservative amino acid change located in the BRCT domain 2 (IPR001357) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251444 control chromosomes (gnomAD). c.5357T>C has been reported in the literature in individuals affected with breast and/or ovarian cancer (Meyer_2003, Lu_2015, Zhang_2017, Shao_2019). These data indicate that the variant may be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant results in similar levels of cell proliferation and apoptosis as the wild-type in transfected cells (Zhang_2017); however, in several other studies the variant was demonstrated to affect protein function, e.g. resulting in decreased transcriptional activity and defective homology-directed repair(Lu_2015, Findlay_2018, Fernandes_2019, Bouwman_2020). Co-occurrence with another pathogenic variant have been reported (BRCA2 c.2818C>T (p.Gln940X), in an internal LCA sample) providing supporting evidence for a benign role. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as VUS (n=3) or likely pathogenic (n=4). Based on the evidence outlined above, the variant was classified as likely pathogenic.

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

Jan 02, 2025

Molecular Pathology, Peter Maccallum Cancer Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 16, 2010

Sharing Clinical Reports Project (SCRP)

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

Mar 25, 2013

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

Jun 01, 2021

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Pathogenic:2

Jan 10, 2020

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in individuals with breast and/or ovarian cancer (Meyer 2003, Zhang 2017); Published functional studies support a damaging effect (Lu 2015, Zhang 2017, Findlay 2018, Fernandes 2019); Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Also known as 5476T>C; This variant is associated with the following publications: (PMID: 26689913, 10811118, 12938098, 29113215, 28726806, 30765603, 30209399, 18069886, 31825140)

May 14, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA1 c.5357T>C (p.Leu1786Pro) variant has been reported in the published literature in individuals with breast and/or ovarian cancer (PMIDs: 26317927 (2016), 12938098 (2003)). Functional evidence suggests that this variant may impact BRCA1 protein function (PMIDs: 30765603 (2019), 30209399 (2018), 26689913 (2015)). The frequency of this variant in the general population, 0.000004 (1/251444 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as likely pathogenic.

Hereditary cancer-predisposing syndrome Pathogenic:2

Jan 22, 2025

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L1786P variant (also known as c.5357T>C), located in coding exon 20 of the BRCA1 gene, results from a T to C substitution at nucleotide position 5357. The leucine at codon 1786 is replaced by proline, an amino acid with similar properties. This alteration has been reported in multiple breast and/or ovarian cancer cohorts (Meyer P et al. Hum. Mutat. 2003 Sep; 22(3):259; Shao D et al. Cancer Sci, 2020 Feb;111:647-657; Wan Q et al. Fam Cancer, 2021 Apr;20:85-95). This alteration was also found to be non-functional in multiple studies (Lu C et al. Nat Commun. 2015 Dec 22;6:10086; Fernandes VC et al. J Biol Chem, 2019 04;294:5980-5992; Zhang H et al. Oncol Lett, 2017 Nov;14:5839-5844; Findlay GM et al. Nature. 2018 10;562:217-222). Based on internal structural assessment, this alteration results in moderate structural disruption of the BRCT domain (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

Jul 20, 2021

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces leucine with proline at codon 1786 of the BRCA1 protein. Computational prediction 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). Functional studies have shown the variant protein to be defective in transcriptional activity (PMID: 30765603), homology-directed DNA repair (PMID: 26689913, 32546644) and in a haploid cell proliferation assay (PMID: 30209399). This variant has been reported in individuals and families affected with breast and ovarian cancer (PMID 12938098, 26689913, 29113215, Color internal data). This variant has been identified in 1/251444 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S Pathogenic:1

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.;Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.;Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.

Triple-negative breast cancer Pathogenic:1

Apr 28, 2025

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Classified according to ClinGen ENIGMA BRCA1 and BRCA2 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BRCA1 Version 1.2.0. Criteria used: PS3_Strong, PM2_Supporting, PP3_Supporting.

Malignant tumor of breast Uncertain:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

The p.Leu1786Pro variant has been reported in the literature in 2 of 251 probands with breast or ovarian cancer (Meyer 2003), but population controls were not included in this study. The p.Leu1786 residue is conserved in mammals but not in lower organisms and computational analyses (SIFT, AlignGVGD) provide inconsistent predictions regarding the impact to the protein and this information is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classfied as a variant of unknown significance.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0	.;T;.;T;T;T;.;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Benign	0.0	.;M;.;.;.;.;.;.
PhyloP100		5.1
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-4.4	D;N;.;.;.;.;N;D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0040	D;D;.;.;.;.;D;D
Sift4G	Uncertain	0.0080	D;D;D;D;D;D;D;D
Vest4		0.96
ClinPred		0.96	D
GERP RS		5.5
Varity_R		0.93
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs398122697; hg19: chr17-41201187;