chr17-43104234-T-G

Position:

• chr17-43104234-T-G

Variant summary

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

The NM_007294.4(BRCA1):​c.329A>C​(p.Lys110Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as not provided (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 0.919

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.329A>C	p.Lys110Thr	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.329A>C	p.Lys110Thr	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: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Familial cancer of breast Other:1

not provided, no classification provided

literature only

ClinVar Staff, National Center for Biotechnology Information (NCBI)

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	.;T;.;.;.;.;.;T;.;T;.;T;T;.;T;T;.;.
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Benign	0.61	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.50	D
MetaRNN	Uncertain	0.69	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Uncertain	2.4	M;M;M;M;.;M;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.90	N;N;N;N;N;N;N;N;N;D;N;.;N;N;N;N;D;.
REVEL	Uncertain	0.64
Sift	Benign	0.15	T;D;D;T;D;T;D;T;T;D;D;.;D;D;D;T;D;.
Sift4G	Benign	0.075	T;T;T;T;T;T;.;.;T;.;T;.;D;.;D;.;.;.
Polyphen		0.92, 1.0, 0.91	.;P;.;.;.;D;.;.;.;.;P;.;.;.;.;.;.;.
Vest4		0.40
MutPred		0.75		Loss of ubiquitination at K110 (P = 0.0043);Loss of ubiquitination at K110 (P = 0.0043);Loss of ubiquitination at K110 (P = 0.0043);Loss of ubiquitination at K110 (P = 0.0043);.;Loss of ubiquitination at K110 (P = 0.0043);.;Loss of ubiquitination at K110 (P = 0.0043);.;.;Loss of ubiquitination at K110 (P = 0.0043);Loss of ubiquitination at K110 (P = 0.0043);Loss of ubiquitination at K110 (P = 0.0043);.;Loss of ubiquitination at K110 (P = 0.0043);Loss of ubiquitination at K110 (P = 0.0043);.;.;
MVP		0.92
MPC		0.16
ClinPred		0.48	T
GERP RS		4.2
Varity_R		0.12
gMVP		0.48

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: rs397509053; hg19: chr17-41256251;