17-43093163-T-C

Variant summary

Our verdict is Likely benign. Variant got -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

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 Likely_benign. Variant got -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 id is 37465.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=5, Benign=4}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.2368A>G	p.Thr790Ala	missense_variant	10/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.2368A>G	p.Thr790Ala	missense_variant	10/23	1	NM_007294.4	P4

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

GnomAD3 exomes AF: 0.0000718 AC: 18 AN: 250612 Hom.: 0 AF XY: 0.0000443 AC XY: 6 AN XY: 135440

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 SAS 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

Gnomad4 AFR exome AF: 0.00188

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000133

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

Gnomad4 AFR AF: 0.000891

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.0000833 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

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 17, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 28, 2020	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. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 08, 2020	This variant is associated with the following publications: (PMID: 15983021, 23192404, 16267036, 22875147, 18284688, 16518693, 31341521, 30606148) -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 01, 2021	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 07, 2015	- -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 12, 2020	- -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Nov 30, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 05, 2019	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. -
Likely benign, criteria provided, single submitter	curation	University of Washington Department of Laboratory Medicine, University of Washington	Mar 23, 2023	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

Benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Nov 25, 2008	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 03, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 13, 2018	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

Uncertain significance, no assertion criteria provided

clinical testing

Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research

Nov 04, 2013

- -

Malignant tumor of breast Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

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

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 30, 2023

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

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;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N;N;N
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs41286298; hg19: chr17-41245180;