rs1464752950

chr17-43099776-C-Achr17-43099776-C-Gchr17-43099776-C-T

Variant summary

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

The NM_007294.4(BRCA1):c.546G>T(p.Leu182Phe) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L182M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: BRCA1 NM_007294.4 missense, splice_region
• Scores: Splicing: ADA: 0.008554
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.690

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	UniProt
BRCA1	NM_007294.4	c.546G>T	p.Leu182Phe	missense_variant, splice_region_variant	7/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.546G>T	p.Leu182Phe	missense_variant, splice_region_variant	7/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Sep 27, 2019

This missense variant replaces leucine with phenylalanine at codon 182 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 01, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 491176). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 182 of the BRCA1 protein (p.Leu182Phe). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
Cadd	Benign	19
Dann	Uncertain	1.0
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.15
FATHMM_MKL	Benign	0.66	D
LIST_S2	Uncertain	0.89	D;D;D;D;D;D;T;D;D;T;D;T;D;D;D;D
M_CAP	Pathogenic	0.55	D
MetaRNN	Uncertain	0.68	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.5	M;M;M;M;.;M;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	0.79	D;D;D;D;D;D;D;D;D;N;N;N;N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.36	N;N;N;N;N;N;N;N;N;N;N;.;N;N;N;N
REVEL	Uncertain	0.62
Sift	Uncertain	0.010	D;D;D;D;D;D;D;D;D;D;D;.;D;D;D;D
Sift4G	Benign	0.73	T;D;D;T;D;T;.;.;T;.;D;.;D;.;D;.
Polyphen		0.99, 1.0, 1.0	.;D;.;.;.;D;.;D;.;.;D;.;.;.;.;.
Vest4		0.50
MutPred		0.49		Loss of catalytic residue at L182 (P = 0.0867);Loss of catalytic residue at L182 (P = 0.0867);Loss of catalytic residue at L182 (P = 0.0867);Loss of catalytic residue at L182 (P = 0.0867);.;Loss of catalytic residue at L182 (P = 0.0867);.;.;.;.;Loss of catalytic residue at L182 (P = 0.0867);Loss of catalytic residue at L182 (P = 0.0867);Loss of catalytic residue at L182 (P = 0.0867);.;Loss of catalytic residue at L182 (P = 0.0867);.;
MVP		0.95
MPC		0.45
ClinPred		0.96	D
GERP RS		1.8
Varity_R		0.20
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0086
dbscSNV1_RF	Benign	0.092
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: rs1464752950; hg19: chr17-41251793;