17-43057075-C-G

Position:

• chr17-43057075-C-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_007294.4(BRCA1):​c.5254G>C​(p.Ala1752Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 U:1 O:1
• Conservation: PhyloP100: 3.19

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.888
• PP5: Variant 17-43057075-C-G is Pathogenic according to our data. Variant chr17-43057075-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 55483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.5254G>C	p.Ala1752Pro	missense_variant	19/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.5254G>C	p.Ala1752Pro	missense_variant	19/23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1 Other:1

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Nov 17, 1998	- -
not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 03, 2022

The p.A1752P pathogenic variant (also known as c.5254G>C and 5373G>C), located in coding exon 18 of the BRCA1 gene, results from a G to C substitution at nucleotide position 5254. The alanine at codon 1752 is replaced by proline, an amino acid with highly similar properties. This alteration has been reported in multiple women with early-onset breast cancer as well as family histories of breast cancer, including multiple reports in Chinese cohorts (Gao X et al. Hum Mutat, 2020 03;41:696-708; Bhaskaran SP et al. Int J Cancer, 2019 08;145:962-973; Li WF et al. Breast Cancer Res Treat, 2008 Jul;110:99-109; Essioux L et al. Am. J. Med. Genet. 1998 Sep;79:175-83; Bergthorsson JT et al. J. Med. Genet. 2001 Jun;38:361-8). Multiple assays find this variant is non-functional (Findlay GM et al. Nature, 2018 10;562:217-222; Lee MS et al. Cancer Res. 2010 Jun;70:4880-90; Phelan CM et al. J. Med. Genet., 2005 Feb;42:138-46). Based on literature and internal structural assessments, this alteration is structurally detrimental by breaking an alpha helix in BRCT domains (Ambry internal data; Karchin R et al. PLoS Comput Biol, 2007 Feb;3:e26; Clapperton JA et al. Nat. Struct. Mol. Biol., 2004 Jun;11:512-8). In addition, this alteration segregated with disease and was associated with family and tumor features that characterize a pathogenic mutation in BRCA1 (Caputo SM et al. Am J Hum Genet, 2021 10;108:1907-1923). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 14, 2023

This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1752 of the BRCA1 protein (p.Ala1752Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 9788557, 11389159, 17851763, 30702160, 31825140). This variant is also known as 5373C>G. ClinVar contains an entry for this variant (Variation ID: 55483). 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: 14534301, 15172985, 15689452, 17305420, 20516115, 30209399). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	.;T;.;.;T;T;.;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Benign	1.9	.;L;.;.;.;.;.;.
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.4	D;N;.;D;.;.;N;D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0030	D;D;.;D;.;.;D;D
Sift4G	Uncertain	0.0070	D;D;D;D;D;D;D;D
Polyphen		0.98, 1.0	.;D;.;.;.;D;.;.
Vest4		0.91
MVP		0.92
MPC		0.13
ClinPred		0.87	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.75
gMVP		0.91

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

Publications

LitVar

Other links and lift over

dbSNP: rs80357074; hg19: chr17-41209092;