17-43094110-A-G

Variant names:

• chr17-43094110-A-G
• rs80357490
• NM_007294.4:c.1421T>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_007294.4(BRCA1):​c.1421T>C​(p.Leu474Ser) 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 Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L474F) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 1.57

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
• BP6: Variant 17-43094110-A-G is Benign according to our data. Variant chr17-43094110-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 805950.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.1421T>C	p.Leu474Ser	missense_variant	Exon 10 of 23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.1421T>C	p.Leu474Ser	missense_variant	Exon 10 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

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

Jan 15, 2020

International Hereditary Cancer Center PUM, Pomeranian Medical University

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The variant coexists with another loss-of-function variant in BRCA1 gene in a breast cancer patient. This strongly suggests that this is a benign variant. -

Hereditary cancer-predisposing syndrome Benign:1

Mar 23, 2023

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D;.;.;.;T;T;.
Eigen	Benign	-0.089
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.73	T;T;T;T;T;T;T
M_CAP	Pathogenic	0.44	D
MetaRNN	Uncertain	0.50	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.34	D
MutationAssessor	Uncertain	2.8	M;M;.;.;.;.;.
PrimateAI	Benign	0.27	T
PROVEAN	Pathogenic	-5.3	D;D;D;D;.;D;D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.026	D;D;D;D;.;D;D
Sift4G	Benign	0.13	T;T;T;T;.;T;.
Polyphen		0.83	P;.;.;D;.;.;.
Vest4		0.36
MutPred		0.57		Loss of loop (P = 0.0031);Loss of loop (P = 0.0031);.;Loss of loop (P = 0.0031);.;Loss of loop (P = 0.0031);.;
MVP		0.92
MPC		0.52
ClinPred		0.56	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.15
gMVP		0.17

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: rs80357490; hg19: chr17-41246127;