rs200449040

Positions:

• chr17-43104150-A-G
• chr17-43104150-A-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_007294.4(BRCA1):​c.413T>C​(p.Leu138Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,776 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 0.0750

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 Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12568739).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.413T>C	p.Leu138Pro	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.413T>C	p.Leu138Pro	missense_variant	6/23	1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251430 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135884

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 SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461776 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 727190

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 15, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 09, 2021	The p.L138P variant (also known as c.413T>C), located in coding exon 5 of the BRCA1 gene, results from a T to C substitution at nucleotide position 413. The leucine at codon 138 is replaced by proline, an amino acid with similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

- -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 28, 2023

ClinVar contains an entry for this variant (Variation ID: 433690). 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 not been reported in the literature in individuals affected with BRCA1-related conditions. This variant is present in population databases (rs200449040, gnomAD 0.003%). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 138 of the BRCA1 protein (p.Leu138Pro). -

Breast-ovarian cancer, familial, susceptibility to, 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Mar 10, 2023

This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	0.060
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.086	.;T;.;.;.;.;.;T;.;T;.;T;T;.;T;T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.085	N
LIST_S2	Benign	0.72	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Uncertain	0.090	D
MetaRNN	Benign	0.13	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N;N;N;N;.;N;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.48	N;N;N;N;N;N;N;N;N;N;N;.;N;N;N;N
REVEL	Uncertain	0.56
Sift	Benign	0.19	T;T;T;T;T;T;T;T;T;T;T;.;T;T;T;T
Sift4G	Benign	0.24	T;T;T;T;T;T;.;.;T;.;T;.;T;.;T;.
Polyphen		0.61, 0.94, 0.95, 0.0	.;P;.;.;.;P;.;P;.;.;B;.;.;.;.;.
Vest4		0.18
MutPred		0.37		Gain of ubiquitination at K135 (P = 0.0499);Gain of ubiquitination at K135 (P = 0.0499);Gain of ubiquitination at K135 (P = 0.0499);Gain of ubiquitination at K135 (P = 0.0499);.;Gain of ubiquitination at K135 (P = 0.0499);.;Gain of ubiquitination at K135 (P = 0.0499);.;.;Gain of ubiquitination at K135 (P = 0.0499);Gain of ubiquitination at K135 (P = 0.0499);Gain of ubiquitination at K135 (P = 0.0499);.;Gain of ubiquitination at K135 (P = 0.0499);Gain of ubiquitination at K135 (P = 0.0499);
MVP		0.55
MPC		0.13
ClinPred		0.19	T
GERP RS		-1.9
Varity_R		0.052
gMVP		0.55

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: rs200449040; hg19: chr17-41256167;