rs876659528

Positions:

• chr17-43104219-G-A
• chr17-43104219-G-C
• chr17-43104219-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_007294.4(BRCA1):​c.344C>T​(p.Pro115Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 3.80

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.344C>T	p.Pro115Leu	missense_variant	6/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.344C>T	p.Pro115Leu	missense_variant	6/23	1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 14, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 12, 2023	The p.P115L variant (also known as c.344C>T), located in coding exon 5 of the BRCA1 gene, results from a C to T substitution at nucleotide position 344. The proline at codon 115 is replaced by leucine, an amino acid with similar properties. This variant has been reported in a Chinese patient with a history of benign breast disease, and in a Chinese patient with a solid pseudopapillary tumor of the pancreas (Suter NM et al. Cancer Epidemiol Biomarkers Prev, 2004 Feb;13:181-9; Yin L et al. JAMA Netw Open, 2022 Feb;5:e2148721). This variant has also been identified Chinese cohort studies of individuals with a personal and/or family history of breast or ovarian cancers undergoing multi-gene panel testing for HBOC risk assessment (Shao D et al. Cancer Sci, 2020 Feb;111:647-657; Yao L et al. J Hum Genet, 2022 Nov;67:639-642). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 06, 2020

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function. This variant has been observed in individual(s) with benign breast disease (PMID: 14973102). ClinVar contains an entry for this variant (Variation ID: 232058). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with leucine at codon 115 of the BRCA1 protein (p.Pro115Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	.;T;.;.;.;.;.;T;.;T;.;T;T;.;T;T;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.73	D
MetaRNN	Uncertain	0.56	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.4	M;M;M;M;.;M;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	0.74	D;D;D;D;D;D;D;D;D;D;D;D;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.6	N;N;N;D;N;D;N;D;N;D;N;.;N;N;N;D;D
REVEL	Uncertain	0.57
Sift	Uncertain	0.010	D;D;D;T;D;T;D;D;D;D;D;.;D;D;D;D;D
Sift4G	Benign	0.20	T;D;D;D;D;D;.;.;D;.;D;.;D;.;D;.;.
Polyphen		0.99, 1.0, 0.93	.;D;.;.;.;D;.;.;.;.;P;.;.;.;.;.;.
Vest4		0.40
MutPred		0.24		Loss of methylation at K110 (P = 0.0464);Loss of methylation at K110 (P = 0.0464);Loss of methylation at K110 (P = 0.0464);Loss of methylation at K110 (P = 0.0464);.;Loss of methylation at K110 (P = 0.0464);.;Loss of methylation at K110 (P = 0.0464);.;.;Loss of methylation at K110 (P = 0.0464);Loss of methylation at K110 (P = 0.0464);Loss of methylation at K110 (P = 0.0464);.;Loss of methylation at K110 (P = 0.0464);Loss of methylation at K110 (P = 0.0464);.;
MVP		0.84
MPC		0.35
ClinPred		0.92	D
GERP RS		4.3
Varity_R		0.068
gMVP		0.39

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: rs876659528; hg19: chr17-41256236; COSMIC: COSV58785195; COSMIC: COSV58785195;