17-43071031-A-G

Position:

• chr17-43071031-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_007294.4(BRCA1):​c.4883T>C​(p.Met1628Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00096 in 1,614,148 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00095 (9 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Benign reviewed by expert panel U:1 B:28 O:1
• Conservation: PhyloP100: -0.667

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015231997).
• BP6: Variant 17-43071031-A-G is Benign according to our data. Variant chr17-43071031-A-G is described in ClinVar as [Benign]. Clinvar id is 41828.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43071031-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0011 (168/152258) while in subpopulation EAS AF= 0.00887 (46/5188). AF 95% confidence interval is 0.00683. There are 2 homozygotes in gnomad4. There are 111 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.4883T>C	p.Met1628Thr	missense_variant	15/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.4883T>C	p.Met1628Thr	missense_variant	15/23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes AF: 0.00110 AC: 168 AN: 152140 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00692

Gnomad EAS AF: 0.00885

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00754

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00147 AC: 370 AN: 251392 Hom.: 1 AF XY: 0.00127 AC XY: 173 AN XY: 135874

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00486

Gnomad EAS exome AF: 0.00430

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.00739

Gnomad NFE exome AF: 0.000457

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.000945 AC: 1382 AN: 1461890 Hom.: 9 Cov.: 31 AF XY: 0.000949 AC XY: 690 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00551

Gnomad4 EAS exome AF: 0.0128

Gnomad4 SAS exome AF: 0.000429

Gnomad4 FIN exome AF: 0.00777

Gnomad4 NFE exome AF: 0.000183

Gnomad4 OTH exome AF: 0.00113

GnomAD4 genome AF: 0.00110 AC: 168 AN: 152258 Hom.: 2 Cov.: 32 AF XY: 0.00149 AC XY: 111 AN XY: 74436

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00692

Gnomad4 EAS AF: 0.00887

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00754

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000698 Hom.: 2

Bravo AF: 0.000351

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00152 AC: 185

Asia WGS AF: 0.00924 AC: 32 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000356

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:28 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1 Benign:8

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Michigan Medical Genetics Laboratories, University of Michigan	Apr 21, 2016	- -
Likely benign, criteria provided, single submitter	literature only	Counsyl	Mar 07, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
Benign, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Aug 10, 2015	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 = 0.00000495. Also class 1 based on frequency >1% in an outbred sampleset. Frequency 0.01399 (Asian), derived from 1000 genomes (2012-04-30). -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 28, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -

not specified Benign:6 Other:1

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 0.8% (51/6614) Finnish; ClinVar: 6 B/LB -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Dec 29, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 22, 2021	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -

Hereditary cancer-predisposing syndrome Benign:4

Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Dec 01, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 30, 2014	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Oct 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 18, 2014	This alteration is classified as 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. -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 12, 2020	- -
Likely benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	BRCA1: BP4, BS1 -

Hereditary breast ovarian cancer syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 04, 2025	- -
Benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Feb 27, 2024	- -
Benign, criteria provided, single submitter	clinical testing	National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	Apr 19, 2022	- -

Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 24, 2022

- -

Breast neoplasm Benign:1

Likely benign, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Malignant tumor of breast Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BRCA1 p.Met1628Thr variant was identified in at least 105 of 111464 proband chromosomes (frequency: 0.001) from individuals or families with breast or ovarian cancer, and was present in 55 of 1140 control chromosomes (frequency: 0.048) (Inoue 1995, Judkins 2005, Ostrow 2004, Phelan 2004, Tavtigian 2006, Tamboom 2010). The variant was listed in dbSNP (ID: rs4986854) “With untested allele”, with a minor allele frequency of 0.004 (1000 Genomes Project); in HapMap-JPT cohort with a frequency of 0.041, and the PAC1 cohort with a frequency of 0.21; and Inoue (1995) found the variant allele at a frequency of 0.39 in a Japanese group of healthy control individuals. The identification of the variant in these population cohorts increases the likelihood that this is a low frequency benign variant in certain populations of origin. The variant was also identified in HGMD, LOVD, the BIC database (96X with unknown clinical importance), and UMD (4X as a neutral variant). In UMD the variant was identified with a co-occurring pathogenic BRCA2 variant (c.4576dup (p.Thr1526AsnfsX3)), and Judkins (2005) observed the variant in trans with three different pathogenic BRCA1 mutations, increasing the likelihood that the p.Met1628Thr variant does not have clinical significance. In addition, a study by Phelan (2004) found that the variant did not segregate with disease in one family, and two functional studies showed no showed no effect of the variant on transcriptional activation (Phelan 2004, Ostrow 2004). Furthermore, Myriad classifies this variant as a polymorphism (personal communication). In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. -

BRCA1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 10, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Uncertain	0.080
CADD	Benign	0.056
DANN	Benign	0.18
DEOGEN2	Benign	0.091	.;T;.;.;T;.;.;.;T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.026	N
LIST_S2	Uncertain	0.86	D;D;D;D;D;D;D;D;D;D
MetaRNN	Benign	0.015	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.1	.;L;.;.;.;.;.;.;.;.
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.59	N;N;.;N;.;N;N;N;N;N
REVEL	Uncertain	0.49
Sift	Benign	0.56	T;T;.;T;.;T;T;T;T;T
Sift4G	Benign	0.29	T;T;T;T;T;T;T;.;.;T
Polyphen		0.039, 0.0030	.;B;.;.;.;.;.;.;B;.
Vest4		0.26
MVP		0.39
MPC		0.094
ClinPred		0.0046	T
GERP RS		-2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.031
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs4986854; hg19: chr17-41223048;