17-43093163-T-C

Variant names:

• chr17-43093163-T-C
• rs41286298
• NM_007294.4:c.2368A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_007294.4(BRCA1):​c.2368A>G​(p.Thr790Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00007 in 1,613,726 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).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000049 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:10
• Conservation: PhyloP100: 0.181
• Publications: 16 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06325126).
• BP6: Variant 17-43093163-T-C is Benign according to our data. Variant chr17-43093163-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 37465.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.2368A>G	p.Thr790Ala	missense_variant	Exon 10 of 23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.2368A>G	p.Thr790Ala	missense_variant	Exon 10 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes AF: 0.000276 AC: 42 AN: 152118 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000894

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.0000718 AC: 18 AN: 250612 AF XY: 0.0000443

Gnomad AFR exome AF: 0.00105

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: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000486 AC: 71 AN: 1461490 Hom.: 0 Cov.: 41 AF XY: 0.0000344 AC XY: 25 AN XY: 727020

African (AFR) AF: 0.00188 AC: 63 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: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53232

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111884

Other (OTH) AF: 0.000133 AC: 8 AN: 60374

GnomAD4 genome AF: 0.000276 AC: 42 AN: 152236 Hom.: 0 Cov.: 32 AF XY: 0.000255 AC XY: 19 AN XY: 74450

African (AFR) AF: 0.000891 AC: 37 AN: 41528

American (AMR) AF: 0.000196 AC: 3 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68008

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000169 Hom.: 0

Bravo AF: 0.000461

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000741 AC: 9

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:2

Jan 28, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA1 c.2368A>G; p.Thr790Ala variant (rs41286298) is reported in the literature in multiple individuals affected with breast cancer (Cortes 2019, Haffty 2006, Lee 2008, Rummel 2013). However, this variant is also reported to co-occur with pathogenic variants in BRCA1 or BRCA2 by other laboratories in ClinVar (Variant ID: 37465), and is found in the African population with an allele frequency of 0.10% (25/24960 alleles) in the Genome Aggregation Database. The threonine at codon 790 is moderately conserved, and computational analyses (SIFT: tolerated, PolyPhen-2: possibly damaging) predict conflicting effects of this variant on protein structure/function. Although there is evidence to support a benign role for this variant, due to insufficent information, the clinical significance of is uncertain at this time. References: Cortes C et al. Mutational analysis of BRCA1 and BRCA2 genes in women with familial breast cancer from different regions of Colombia. Hered Cancer Clin Pract. 2019 Jul 15;17:20. Haffty BG et al. Racial differences in the incidence of BRCA1 and BRCA2 mutations in a cohort of early onset breast cancer patients: African American compared to white women. J Med Genet. 2006 Feb;43(2):133-7. Lee E et al. Evaluation of unclassified variants in the breast cancer susceptibility genes BRCA1 and BRCA2 using five methods: results from a population-based study of young breast cancer patients. Breast Cancer Res. 2008;10(1):R19. Rummel S et al. Evaluation of BRCA1 mutations in an unselected patient population with triple-negative breast cancer. Breast Cancer Res Treat. 2013 Jan;137(1):119-25. -

Oct 01, 2021

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Thr790Ala variant in BRCA1 has been reported in at >10 individuals with breast or ovarian cancer, the majority of which were Black or African-American (Haffty 2005 PMID: 15983021, Lee 2008 PMID: 18284688, Rummel 2013 PMID: 23192404, Pal 2015 PMID: 26287763, Cortes 2019 PMID: 31341521, Cotrim 2019 PMID: 30606148; Breast Cancer information Core (BIC)). It has also been identified in 0.1% (25/24960) of African or African-American chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has been reported in ClinVar (Variation ID 37465). Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, including the presence of Alanine (Ala) at this position in two mammals, though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of this variant is uncertain, these frequency and lack of conservation suggest that it is more likely to be benign. ACMG/AMP Criteria applied: PS4_Moderate, BP4, BS1_Supporting. -

Aug 17, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 08, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 15983021, 23192404, 16267036, 22875147, 18284688, 16518693, 31341521, 30606148) -

Apr 07, 2015

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:3

Nov 30, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Mar 05, 2019

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. -

Feb 12, 2020

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 23, 2023

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -

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

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 25, 2008

Sharing Clinical Reports Project (SCRP)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:2

Jan 03, 2022

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 13, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRCA1 c.2368A>G (p.Thr790Ala) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.9e-05 in 282008 control chromosomes, predominantly within the African subpopulation at a frequency of 0.001 in the gnomAD database. This frequency is about the same as expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (0.001 vs 0.001), suggesting a benign role for the variant. c.2368A>G has been reported in the literature in several individuals of African and/or African American ancestry affected with Hereditary Breast and Ovarian Cancer. Due to the similarity in the ethnicity between control chromosomes and published reports, these occurrences do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic BRCA1 variants have been reported in the UMD database (c.5324T>G (p.Met1775Arg) in one individual and c.1961dup (p.Tyr655valfsX18) in another), in addition, several co-occurrences with pathogenic BRCA2 variants have also been reported (in the BIC database: c.5946_5946delT (p.Ser1982fsX22) in one individual, and c.8948_8953+5delATTCAGGTAAG in two other individuals; and in LCA internal samples: c.2808delA (p.Lys936fsX24) in one individual and c.5351dupA (p.Asn1784fsX3) in another individual). These multiple co-occurrences strongly support a benign role for the variant. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as Benign (1x) / Likely benign (2x). Based on the evidence outlined above, the variant was re-classified as benign. -

Breast and/or ovarian cancer Uncertain:1

Nov 04, 2013

Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Malignant tumor of breast Uncertain:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRCA1 p.Thr790Ala variant was identified in the literature in an African American individual with breast cancer; however, control chromosomes from healthy individuals were not evaluated in this study (Haffty 2005). The variant was also identified in dbSNP (ID: rs41286298) “With unknown allele”, BIC (8X with unknown clinical importance) and UMD (1X as an unclassified variant). Within the UMD record, the variant was noted to co-occur with a known pathogenic mutation in BRCA1 (c.5324T>G (p.Met1775Arg)), increasing the likelihood that the p.Thr790Ala variant may not have clinical significance. In addition, the variant was reported in three of 4460 African American chromosomes (frequency: 0.0007) from the Exome Variant Server ESP Project, increasing the likelihood that may be a low frequency benign variant in certain populations of origin. The p.Thr790 residue is conserved in mammals; however, computational analyses (PolyPhen-2, SIFT, AlignGVGD) provide inconsistent predictions regarding the impact to the protein and this information is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance. -

BRCA1-related disorder Benign:1

May 30, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Hereditary breast ovarian cancer syndrome Benign:1

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	13
DANN	Benign	0.83
DEOGEN2	Uncertain	0.53	D;.;.;.;T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.067	N
LIST_S2	Benign	0.77	T;T;T;T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.063	T;T;T;T;T
MetaSVM	Benign	-0.40	T
MutationAssessor	Uncertain	2.3	M;M;.;.;.
PhyloP100		0.18
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-3.9	D;D;D;D;.
REVEL	Uncertain	0.50
Sift	Benign	0.059	T;T;T;D;.
Sift4G	Benign	0.095	T;T;T;D;.
Polyphen		0.93	P;.;.;P;.
Vest4		0.32
MVP		0.71
MPC		0.15
ClinPred		0.13	T
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.066
gMVP		0.14
Mutation Taster		=0/100	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: rs41286298; hg19: chr17-41245180;