NM_007294.4:c.5324T>A

Variant names:

• chr17-43051071-A-T
• rs41293463
• NM_007294.4:c.5324T>A

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3 PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_007294.4(BRCA1):​c.5324T>A​(p.Met1775Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV005836623: Experimental studies have shown that this missense change affects BRCA1 function (PMID:18285836, 20516115, 30209399)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1775L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:9
• Conservation: PhyloP100: 5.03
• Publications: 153 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):

• BRCA1-related cancer predisposition

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• breast-ovarian cancer, familial, susceptibility to, 1

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

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), 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: Pathogenic. The variant received 20 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV005836623: Experimental studies have shown that this missense change affects BRCA1 function (PMID: 18285836, 20516115, 30209399).; SCV001736649: Functional studies have shown that the mutant protein is highly defective for specific phosphopeptide recognition and transcriptional activity (PMID: 18285836, 20516115). This variant has also been reported to cause loss of BRCA1 function in a haploid cell proliferation assay (PMID: 30209399).; SCV002646820: This alteration, as well as a known pathogenic close match alteration BRCA2 p.M1775R, were non-functional in many different assays including a colony size assay, a haploid cell survival assay, multiple transcription activation assays, and multiple protein binding and specificity assays (Thouvenot P et al. PLoS Genet. 2016 06;12:e1006096; Findlay GM et al. Nature. 2018 10;562:217-222; Lee MS et al. Cancer Res. 2010 Jun;70:4880-90; Tischkowitz M et al. Eur. J. Hum. Genet. 2008 Jul;16:820-32; Drikos I et al. Proteins. 2009 Nov;77:464-76).
• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 18 benign, 81 uncertain in NM_007294.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-43051071-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 825652.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.899
• PP5: Variant 17-43051071-A-T is Pathogenic according to our data. Variant chr17-43051071-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 17695.Status of the report is reviewed_by_expert_panel, 3 stars.

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.5324T>A	p.Met1775Lys	missense	Exon 20 of 23	NP_009225.1	P38398-1
	BRCA1	NM_001407581.1		c.5390T>A	p.Met1797Lys	missense	Exon 21 of 24	NP_001394510.1	A0A2R8Y7V5
	BRCA1	NM_001407582.1		c.5390T>A	p.Met1797Lys	missense	Exon 21 of 24	NP_001394511.1	A0A2R8Y7V5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	ENST00000357654.9	TSL:1 MANE Select	c.5324T>A	p.Met1775Lys	missense	Exon 20 of 23	ENSP00000350283.3	P38398-1
	BRCA1	ENST00000471181.7	TSL:1	c.5387T>A	p.Met1796Lys	missense	Exon 21 of 24	ENSP00000418960.2	P38398-7
	BRCA1	ENST00000470026.6	TSL:1	c.5324T>A	p.Met1775Lys	missense	Exon 20 of 23	ENSP00000419274.2	P38398-1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
5	-	-	Breast-ovarian cancer, familial, susceptibility to, 1 (5)
2	-	-	Hereditary breast ovarian cancer syndrome (2)
2	-	-	Hereditary cancer-predisposing syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		5.0
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-4.3	D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.98
MVP		0.96
MPC		0.56
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.95
gMVP		0.87
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.010		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: rs41293463; hg19: chr17-41203088;