17-43094852-C-G

Position:

• chr17-43094852-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_007294.4(BRCA1):​c.679G>C​(p.Glu227Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E227K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.545

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18449166).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.679G>C	p.Glu227Gln	missense_variant	10/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.679G>C	p.Glu227Gln	missense_variant	10/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Benign	15
DANN	Benign	0.93
DEOGEN2	Benign	0.11	T;.;.;.;.;.;T;.;T;.;T;T;.;T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.45
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.85	T;T;T;T;T;D;T;T;D;T;D;T;T;T
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.18	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.46	D
MutationAssessor	Benign	1.6	L;L;L;.;L;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.35	N;N;N;N;N;N;N;N;N;N;.;N;N;N
REVEL	Uncertain	0.56
Sift	Benign	0.048	D;D;D;D;D;T;D;D;T;D;.;T;D;D
Sift4G	Benign	0.19	T;T;T;T;T;.;.;T;.;T;.;T;.;T
Polyphen		0.051	B;.;.;.;B;.;B;.;.;P;.;.;.;.
Vest4		0.45
MutPred		0.17		Loss of glycosylation at S229 (P = 0.095);Loss of glycosylation at S229 (P = 0.095);Loss of glycosylation at S229 (P = 0.095);.;Loss of glycosylation at S229 (P = 0.095);.;.;.;.;Loss of glycosylation at S229 (P = 0.095);.;Loss of glycosylation at S229 (P = 0.095);.;Loss of glycosylation at S229 (P = 0.095);
MVP		0.88
MPC		0.095
ClinPred		0.062	T
GERP RS		1.7
Varity_R		0.050
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-41246869;