17-43104201-T-C

Position:

• chr17-43104201-T-C

Variant summary

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

The NM_007294.4(BRCA1):​c.362A>G​(p.Glu121Gly) 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, single submitter U:1
• Conservation: PhyloP100: 4.30

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 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.362A>G	p.Glu121Gly	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.362A>G	p.Glu121Gly	missense_variant	6/23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2017

In summary, this variant 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 do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a BRCA1-related disease. This sequence change replaces glutamic acid with glycine at codon 121 of the BRCA1 protein (p.Glu121Gly). The glutamic acid residue is moderately conserved and there is a moderate physicochemical difference between glutamic acid and glycine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	.;T;.;.;.;.;.;T;.;T;.;T;T;.;T;T;.
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Uncertain	0.48	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.52	T
MutationAssessor	Uncertain	2.4	M;M;M;M;.;M;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-2.0	N;N;N;N;N;N;N;D;N;D;N;.;N;N;N;D;D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0080	D;D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D
Sift4G	Benign	0.070	T;D;D;D;D;D;.;.;D;.;D;.;D;.;D;.;.
Polyphen		0.98, 1.0, 0.99	.;D;.;.;.;D;.;.;.;.;D;.;.;.;.;.;.
Vest4		0.57
MutPred		0.27		Gain of MoRF binding (P = 0.0483);Gain of MoRF binding (P = 0.0483);Gain of MoRF binding (P = 0.0483);Gain of MoRF binding (P = 0.0483);.;Gain of MoRF binding (P = 0.0483);.;Gain of MoRF binding (P = 0.0483);.;.;Gain of MoRF binding (P = 0.0483);Gain of MoRF binding (P = 0.0483);Gain of MoRF binding (P = 0.0483);.;Gain of MoRF binding (P = 0.0483);Gain of MoRF binding (P = 0.0483);.;
MVP		0.94
MPC		0.44
ClinPred		0.87	D
GERP RS		5.3
Varity_R		0.13
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: rs1555596419; hg19: chr17-41256218;