17-43104895-C-G

Position:

• chr17-43104895-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_007294.4(BRCA1):​c.274G>C​(p.Ala92Pro) 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A92A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3 O:1
• Conservation: PhyloP100: 4.63

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.868

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.274G>C	p.Ala92Pro	missense_variant	5/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.274G>C	p.Ala92Pro	missense_variant	5/23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 16, 2020	This missense variant replaces alanine with proline at codon 92 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 reported 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

Labcorp Genetics (formerly Invitae), Labcorp

May 28, 2015

In summary, this is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. This variant has not been published in the literature and is not present in population databases. This sequence change replaces alanine with proline at codon 92 of the BRCA1 protein (p.Ala92Pro). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and proline. -

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

not provided, no classification provided

in vitro

Brotman Baty Institute, University of Washington

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	.;T;.;.;.;.;.;T;.;T;.;T;T;.;T;T;.;.
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Uncertain	2.5	M;M;M;M;.;M;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.44	N;N;N;N;N;N;N;N;N;N;N;.;N;N;N;D;D;.
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0030	D;D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;.
Sift4G	Benign	0.063	T;D;D;T;D;T;.;.;D;.;D;.;D;.;D;.;.;.
Polyphen		1.0, 1.0	.;D;.;.;.;D;.;.;.;.;D;.;.;.;.;.;.;.
Vest4		0.89
MutPred		0.46		Gain of methylation at K88 (P = 0.0888);Gain of methylation at K88 (P = 0.0888);Gain of methylation at K88 (P = 0.0888);Gain of methylation at K88 (P = 0.0888);.;Gain of methylation at K88 (P = 0.0888);.;Gain of methylation at K88 (P = 0.0888);.;.;Gain of methylation at K88 (P = 0.0888);Gain of methylation at K88 (P = 0.0888);Gain of methylation at K88 (P = 0.0888);.;Gain of methylation at K88 (P = 0.0888);Gain of methylation at K88 (P = 0.0888);.;.;
MVP		1.0
MPC		0.50
ClinPred		0.99	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.85
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs863224755; hg19: chr17-41256912;