NM_007294.4:c.53T>C

Variant names:

• chr17-43124044-A-G
• rs80356929
• NM_007294.4:c.53T>C
• BRCA1 p.Met18Thr

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3 PM1 PM5 PP3_Strong PP5_Very_Strong

The NM_007294.4(BRCA1):​c.53T>C​(p.Met18Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,388 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: "SCV000186729: This alteration has been detected in multiple individuals diagnosed with breast and/or ovarian cancer and has been associated with a significant reduction in homologous-directed recombination activity compared with wild type BRCA1 (p<0.001) (Langston AA et al. N. Engl. J. Med. 1996" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M18I) has been classified as Uncertain significance. The gene BRCA1 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:19 U:1
• Conservation: PhyloP100: 4.17
• Publications: 53 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, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• 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

Specifications for BRCA1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000186729: This alteration has been detected in multiple individuals diagnosed with breast and/or ovarian cancer and has been associated with a significant reduction in homologous-directed recombination activity compared with wild type BRCA1 (p<0.001) (Langston AA et al. N. Engl. J. Med. 1996; 334:137-42, Greenman J et al. Genes Chromosomes Cancer 1998; 21:244-9, Malone KE et al. JAMA 1998; 279:922-9, Ransburgh DJ et al. Cancer Res., 2010 Feb;70:988-95; Towler WI et al. Hum. Mutat. 2013; 34:439-45; Kechin A et al. Breast Cancer Res Treat, 2023 Jan;197:387-395). This alteration also demonstrated reduced ubiquitin ligase activity and BARD1 binding activity as compared to wild type (Whiley PJ et al. PLoS ONE, 2014 Jan;9:e86836; Starita LM et al. Genetics. 2015 Jun;200(2):413-22). An additional functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222).; SCV000909428: Multiple functional studies have reported that this variant impacted BRCA1 function in homology-directed repair and cell proliferation assays (PMID: 21372787, 23867111, 24489791, 30219179, 30209399).; SCV000210063: Functional studies have found discordant results with respect to ubiquitin ligase activity and BARD1 binding, but have revealed impaired homology-directed repair activity, increased centrosome amplification, and loss of ability to rescue cell growth (Ruffner 2001, Morris 2004, Morris 2006, Sarkar 2008, Ransburgh 2010, Parvin 2011, Kais 2012, Bouwman 2013, Towler 2013, Starita 2015).; SCV004219460: Published functional studies have shown that this variant results in a deleterious effect on BRCA1 protein function (PMID: 11320250 (2001), 23161852 (2013), 23867111 (2013), 25823446 (2015), 30209399 (2018)).; SCV001429658: Non-functional in SGE haploid BRCA1-assay (Findlay et al. 2018) (PS3_strong).; SCV001478704: "In functional analyses, multiple studies have reported deleterious effects of the variant, including centrosome amplification, defective BRCA1-mediated homologous repair, defective double-strand break repair, and defective homology-directed recombination (HDR) (Kais_2013, Parvin_2011, Ransburgh_2010, Towler_2013) (ACMG, PS3)."; SCV001575134: Experimental studies have shown that this missense change affects BRCA1 function (PMID: 20103620, 21725363, 23161852, 23867111, 25823446, 27272900).; SCV004847904: In vitro functional studies are conflicting as to the effect of this variant on protein function (Ruffner 2001, Easteron 2007, Sarkar 2008, Millot 2011, Ransburgh 2010, Parvin 2011, Kais 2012, Lindor 2012, Bouwman 2013, Towler 2013, Whiley 2014, Starita 2016, Thouvenot 2016, Findlay 2018)
• PM1: In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 16 benign, 80 uncertain in NM_007294.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-43124044-A-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 531241.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.94
• PP5: Variant 17-43124044-A-G is Pathogenic according to our data. Variant chr17-43124044-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 37664.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.53T>C	p.Met18Thr	missense	Exon 2 of 23	NP_009225.1	P38398-1
	BRCA1	NM_001407581.1		c.53T>C	p.Met18Thr	missense	Exon 2 of 24	NP_001394510.1	A0A2R8Y7V5
	BRCA1	NM_001407582.1		c.53T>C	p.Met18Thr	missense	Exon 2 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.53T>C	p.Met18Thr	missense	Exon 2 of 23	ENSP00000350283.3	P38398-1
	BRCA1	ENST00000471181.7	TSL:1	c.53T>C	p.Met18Thr	missense	Exon 2 of 24	ENSP00000418960.2	P38398-7
	BRCA1	ENST00000470026.6	TSL:1	c.53T>C	p.Met18Thr	missense	Exon 2 of 23	ENSP00000419274.2	P38398-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461388 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 727020

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39650

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111646

Other (OTH) AF: 0.00 AC: 0 AN: 60360

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
6	1	-	Breast-ovarian cancer, familial, susceptibility to, 1 (7)
6	-	-	not provided (6)
4	-	-	Hereditary breast ovarian cancer syndrome (4)
2	-	-	Hereditary cancer-predisposing syndrome (2)
1	-	-	Inherited ovarian cancer (without breast cancer) (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.21	D
MutationAssessor	Benign	0.56	N
PhyloP100		4.2
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.33	N
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.014	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.87
gMVP		0.68
Mutation Taster		=0/100	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs80356929;

hg19: chr17-41276061;