chr17-43067641-T-C

Variant names:

• chr17-43067641-T-C
• rs876659314
• NM_007294.4:c.5041A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B.

Score: 2 - Uncertain Significance

2

PM1PM2BP6_Moderate

The NM_007294.4(BRCA1):​c.5041A>G​(p.Thr1681Ala) 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. T1681N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 30)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.31
• Publications: 10 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 2 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 11 benign, 16 uncertain in NM_007294.4
• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 17-43067641-T-C is Benign according to our data. Variant chr17-43067641-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 868956.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.5041A>G	p.Thr1681Ala	missense_variant	Exon 16 of 23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.5041A>G	p.Thr1681Ala	missense_variant	Exon 16 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 30

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Benign:1

Dec 11, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	.;T;.;.;T;.;.;.;T;.
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.88	D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.49	D
MetaRNN	Uncertain	0.46	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.33	T
MutationAssessor	Uncertain	2.5	.;M;.;.;.;.;.;.;.;.
PhyloP100		3.3
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.3	D;N;.;D;.;N;D;D;N;D
REVEL	Uncertain	0.57
Sift	Uncertain	0.015	D;D;.;D;.;D;D;D;D;D
Sift4G	Benign	0.068	T;D;D;D;D;D;T;.;.;D
Polyphen		0.0, 0.49	.;B;.;.;.;.;.;.;P;.
Vest4		0.58
MVP		0.79
MPC		0.079
ClinPred		0.88	D
GERP RS		4.1
Varity_R		0.58
gMVP		0.70

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: rs876659314; hg19: chr17-41219658;