17-43092490-A-T

Variant names:

• chr17-43092490-A-T
• rs80357020
• NM_007294.4:c.3041T>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_007294.4(BRCA1):​c.3041T>A​(p.Met1014Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,722 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1014I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:1
• Conservation: PhyloP100: 0.247
• Publications: 12 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.17400199).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007294.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	NM_007294.4	MANE Select	c.3041T>A	p.Met1014Lys	missense	Exon 10 of 23	NP_009225.1
	BRCA1	NM_001407581.1		c.3041T>A	p.Met1014Lys	missense	Exon 10 of 24	NP_001394510.1
	BRCA1	NM_001407582.1		c.3041T>A	p.Met1014Lys	missense	Exon 10 of 24	NP_001394511.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	ENST00000357654.9	TSL:1 MANE Select	c.3041T>A	p.Met1014Lys	missense	Exon 10 of 23	ENSP00000350283.3
	BRCA1	ENST00000471181.7	TSL:1	c.3041T>A	p.Met1014Lys	missense	Exon 10 of 24	ENSP00000418960.2
	BRCA1	ENST00000470026.6	TSL:1	c.3041T>A	p.Met1014Lys	missense	Exon 10 of 23	ENSP00000419274.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 251136 AF XY: 0.0000368

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000529

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461722 Hom.: 0 Cov.: 51 AF XY: 0.00000825 AC XY: 6 AN XY: 727166

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53340

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000719 AC: 8 AN: 1111954

Other (OTH) AF: 0.0000331 AC: 2 AN: 60390

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000494 AC: 6

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	1	Hereditary cancer-predisposing syndrome (4)
-	2	-	Breast-ovarian cancer, familial, susceptibility to, 1 (2)
-	2	-	not provided (2)
-	1	-	BRCA1-related cancer predisposition (1)
-	1	-	Hereditary breast ovarian cancer syndrome (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	9.3
DANN	Benign	0.80
DEOGEN2	Uncertain	0.60	D
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.075	N
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		0.25
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.025	D
Polyphen		0.25	B
Vest4		0.42
MutPred		0.43		Gain of ubiquitination at M1014 (P = 0.0039)
MVP		0.75
MPC		0.15
ClinPred		0.098	T
GERP RS		1.4
Varity_R		0.33
gMVP		0.44
Mutation Taster		=22/78	disease causing

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: rs80357020; hg19: chr17-41244507; COSMIC: COSV100523864; COSMIC: COSV100523864;