rs80357103

Variant names:

• chr17-43094640-C-A
• rs80357103
• ENST00000497488.2:c.3G>T

Your query was ambiguous. Multiple possible variants found:

• chr17-43094640-C-A
• chr17-43094640-C-G
• chr17-43094640-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 12P and 8B. PVS1 PS1_Moderate PM2 BP6_Very_Strong

The ENST00000497488.2(BRCA1):​c.3G>T​(p.Met1?) variant causes a start lost 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 Benign (★★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 ENST00000497488.2 start_lost
• Clinical Significance: Benign reviewed by expert panel B:1
• Conservation: PhyloP100: 1.53
• Publications: 15 publications found

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 Gene-Disease associations (from GenCC):

• breast-ovarian cancer, familial, susceptibility to, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Fanconi anemia, complementation group S

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• pancreatic cancer, susceptibility to, 4

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary breast ovarian cancer syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 457 pathogenic variants. Next in-frame start position is after 235 codons. Genomic position: 43093940. Lost 0.149 part of the original CDS.
• PS1: Another start lost variant in ENST00000497488.2 (BRCA1) was described as [Pathogenic] in ClinVar
• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 17-43094640-C-A is Benign according to our data. Variant chr17-43094640-C-A is described in ClinVar as Benign. ClinVar VariationId is 812549.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.891G>T	p.Met297Ile	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.891G>T	p.Met297Ile	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: Benign

Submissions summary: Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

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

Jun 18, 2019

Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000632 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.53	D;.;.;.;T;T;.;.;T
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.88	D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.069	D
MetaRNN	Uncertain	0.45	T;T;T;T;T;T;T;D;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Uncertain	2.4	M;M;.;.;.;.;.;.;.
PhyloP100		1.5
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.2	D;D;D;D;.;D;D;D;D
REVEL	Uncertain	0.59
Sift	Uncertain	0.023	D;D;D;D;.;D;D;D;D
Sift4G	Benign	0.061	T;T;T;T;.;T;.;T;D
Polyphen		0.074	B;.;.;B;.;.;.;.;.
Vest4		0.38
MutPred		0.42		Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);.;Gain of helix (P = 0.0325);.;Gain of helix (P = 0.0325);.;.;Gain of helix (P = 0.0325);
MVP		0.90
MPC		0.098
ClinPred		0.86	D
GERP RS		4.0
Varity_R		0.27
gMVP		0.19

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

Other links and lift over

dbSNP: rs80357103; hg19: chr17-41246657;